CA2160795A1

CA2160795A1 - Heterocyclic derivatives

Info

Publication number: CA2160795A1
Application number: CA002160795A
Authority: CA
Inventors: George Robert Brown; Paul Robert Owen Whittamore; David Robert Brittain
Original assignee: Individual
Current assignee: Syngenta Ltd
Priority date: 1993-04-29
Filing date: 1994-04-28
Publication date: 1994-11-10
Also published as: EP0696284A1; NO954323L; AU6576494A; JPH08509488A; FI955164A; CN1121718A; NO954323D0; WO1994025459A1; IL109451A0; FI955164A0; GB9408473D0; US5919793A

Abstract

Compounds of formula (I) wherein R1 is hydrogen or hydroxy; R2 is hydrogen; or R1 and R2 are joined together so that CR1-CR2 is a double bond;
X is selected from -CH2CH2-, -CH=CH-, -CC-, -CH2O-, -OCH2-, CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n-, and -S(O)nCH2- (wherein n is 0, 1 or 2); Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, carbamoyl, (1-6C) alkylcarbamoyl, di-[(1-6C)alkyl]carbamoyl, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of said oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di[(1-6C)alkyl]carbamoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy; and wherein Ar may bear further substituents; and their pharmaceutically acceptable salts inhibit squalene synthese and are hence useful in lowering cholesterol levels in blood plasma. Processes for preparing compounds of formula (I) are also referred to as well as pharmaceutical compositions containing them and their use in medicine.

Description

W O 94/25459 2 ~ ~3 0 ~ ~ S PCT/GB94/00910 ~ LIC D B IVATIV%S

This invention concerns heterocyclic derivatives vhich are useful in inhibiting squalene synthase, processes for their preparation and pharmaceutical compositions containing them. The present invention is also concerned with methods of using such heterocyclic derivatives in treating diseases and medical conditions Yhere inhibition of squalene synthase is desirable, for example in treating diseases or medical conditions such as hypercholesterolemia and atherosclerosis.
Several different classes of compounds have been reported to possess the capability of being able to loYer cholesterol levels in blood plasma. For example agents ~hich inhibit the enzyme HHG CoA reductase, which is essential for the production of cholesterol, have been reported to reduce levels of serum cholesterol. Illustrative of this class of compounds is the HhG CoA reductase inhibitor knovn as lovastatin vhich is disclosed in US Patent No 4,231,938. Other agents Yhich are reported to lover serum cholesterol incl-~de those Yhich act by complexing vith bile acids in the intestinal system and vhich are hence termed ~blle acid sequestrantsr. It is believed that many of such agents act by sequestering bile acids Yithin the intestinal tract. This results in a lovering of the levels of bile acid circulating in the enteroheptatic system and promoting replacement of bile acids by synthesis in the liver from cholesterol, ~hich results in an upregulation of the heptatic LDL
receptor and thus in a loYering of circulating blood cholesterol levels.
Squalene synthase (also referred to in the art as squalene synthetase) is a microsomal enzyme ~hich catalyses the first committed step of cholesterol biosynthesis. TYO molecules of farnesyl pyrophosphate (FPP) are condensed in the presence of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to form squalene.
The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathYays to ubiquinone, dolichol and isopentenyl t-RNA. Elevated cholesterol levels are known to be one of the main risk factors for ischaemic cardiovacsular disease. Thus, an agent vhich inhibits squalene synthase should be useful in treating diseases and medical conditions in which a reduction in the levels of cholesterol is desirable, for example hypercholesterolemia and atherosclerosis.

216079~

Thus far, the design of squalene synthase inhibitors has concentrated on the preparation of analogues of the substrate farnesyl pyrophosphate (FPP), and hence on compounds which contain phosphorus groups. For example, the preparatlon of phosphorous-containing squalene synthase inhibitors is reported in published European Patent Application No. 409,181; and the preparation of isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthase is reported by Biller et al, J. Hed. Chem., 1988, 31, 1869.
The present invention is based on the discovery that certain heterocyclic derivatives are inhibitors of squalene synthase, and are hence useful in treating diseases and medical conditions in vhich inhibltion of squalene synthase ls desirable.
According to the present invention there is provided a compound of formula I (formula set out hereinafter together vith the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, wherein:
Rl is hydrogen or hydroxy;
R2 is hydrogen; or Rl and R2 are ~oined together so that CR1-CR2 is a double bond;
X is selected from -CH2CH2-, -CH.CH-, -C~C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (vherein n is 0,1 or 2);
~r is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-l(1-6C)alkyllamino, carbamoyl, (1-6C)alkylcarbamoyl, di-l(1-6C)alkyllcarbamoyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-dil(1-6C)alkylcarbamoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, W O 94/25459 21~ PCT/GB94/00910 (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxyi and vherein ~r and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected fron halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; provided that vhen X ls -OCH2-, -NHCH2- or -S(O)nCH2- (vherein n is 0,1 or 2), then R1 is not hydroxy; and provided that vhen a substituent on Ar includes a phenyl moiety, ~ is -OCH2-, then R1 and R2 are not both hydrogen, or ~oined together so that CR -CR is a double bond.
In particular, according to the present invention there is provided a compound of formula I (formula set out hereinafter together vith the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, vherein:
Rl is hydrogen or hydroxy;
R is hydrogen; or R1 and R2 are ~oined together so that CR1-CR2 is a double bond;
is selected from -CH2CH2-, -CH~CH-, -C~C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2C0-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (vherein n is 0,1 or 2);
Ar is phenyl vhich bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyllamino, carbamoyl, (1-6C)alkylcarbamoyl, di-1(1-6C)alkyl]carbamoyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl vhen substituted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime 21~0~9~

derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, N-(1-6C)alkylcarbamoyl, N,N-dil(1-6C)alkylcarbamoyl, amino, (1-6C)alkylamino, di-l(1-6C)alkyllamino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;
and vherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; provided that vhen ~ is -OCH2-, -NHCH2- or -S(O)nCH2- (vherein n is 0,1 or 2), then R1 is not hydroxy; and provided that vhen a substituent on Ar includes a phenyl moiety, then R1 is hydroxy.
It vill be understood that vhen formula I compounds contain a chiral centre, the compounds of the invention may exist in, and be isolated in, optically active or racemic form. The invention includes any optically active or racemic form of a compound of formula I which possesses the beneficial pharmacological effect of inhibiting squalene synthase. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well knovn in the art, for example by, resolution of a racemic form, by synthesis from optically active starting materials or by asymmetric synthesis.
It vill also be understood that, insofar as certain of the compounds of the formula I may exist as geometric isomers the present invention includes any such isomer which possesses the beneficial pharmacological effect of inhibiting squalene synthase.
It is also to be understood that generic terms such as "alkyl" include both the straight chain and branched chain groups such as butyl and tert-butyl. However, when a specific term such as W 0 94/25459 21~ ~ ~ 9 S PCT/GB94/00910 "butyl" ls used, it is specific for the straight chain or "normal"
butyl group, branched chain isomers such as "t-butyl" being referred to specifically vhen intended.
It Yill be appreciated that vhen Rl and R2 are ~oined so that CR1-CR2 is a double bond, the heterocyclic ring in formula I vill comprise the 2,3-dehydroquinuclidine moiety shovn in formula Ia.
A particular value for a group vhich may be present on Ar is, for example, for alkyl; (1-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl;
for alkenyl; (2-4C)alkenyl, such as allyl, prop-2-enyl, but-2-enyl or 2-methyl-2-propenyl;
for alkynyl; (2-4C)alkynyl, such as prop-2-ynyl or but-2-ynyl;
for alkoxy; (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy;
for alkylamino; (1-4C)alkylamino, such as methylamino, ethylamino, propylamino or butylamino;
for di-alkylamino; di-l(1-4C)alkylamino, such as dimethylamino, diethylamino, methylpropylamino or dipropylamino;
for alkylcarbamoyl; N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl;
for di-alkylcarbamoyl; N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl;
for alkoxycarbonyl; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
for alkoxycarbonyl- methoxycarbonylmethyl, methoxycarbonylethyl, alkyl ethoxycarbonylethyl or ethoxycarbonylmethyl;
for alkylthio; methylthio, ethylthio, propylthio, isopropylthio or butylthio;
for alkylsulphinyl; methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl or butylsulphinyl;
for alkylsulphonyl; methylsulphonyl, ethylsulphonyl, propylsulphonyl, isoproylsulphonyl or butylsulphonyl;

21~9~
WO 94/25459 ` PCT/GB94/00910 for halogeno; fluoro, chloro, bromo or iodo;
for halogenoalkyl; halogenoalkyl containing one, tvo or three halo groups selected from fluoro, chloro, bromo and iodo and an alkyl group selected from methyl, ethyl, propyl, iso-propyl, butyl, lso-butyl and sec-butyl, (in particular fluoromethyl, difluoromethyl or trifluoromethyl);
for alkanoyl; formyl, acetyl, propionyl and butyryl;
for 0-(1-6C)alkyl methyl, ethyl, propyl, isopropyl and butyl ethers ethers of alkanoyl of said oximes;
oximes for alkenyloxy; allyloxy and propenyloxy; and for (1-4C)alkylenedioxy methylenedioxy, ethylenedioxy and trimethylenedioxy for alkanoylamino; formamido, acetamido, propionamido, lso-propionamido, butyramido or iso-butyramido;
for alkoxyalkoxy; methoxyethoxy, ethoxymethoxy, ethoxyethoxy and methoxymethoxy;
for alkanoyloxy; acetyloxy and propionyloxy; and for alkanoyloxyalkyl; acetyloxymethyl, acetyloxyethyl, propionyloxymethyl and propionyloxy ethyl In particular Ar is phenyl ~hich bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkoxy(1-6C)alkyll(1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxycarbonyl, di-l(1-6C)alkoxyl(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl, di-l(1-6C)alkyllamino(1-6C)alkyl, (1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-I(1-6C)alkyl~carba~oyl(1-6C)alkyl;
(1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy, cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy, nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio, W O 94/25459 21~ 9 ri PCT/GB94/00910 (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)-alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkyl, carboxy(1-6C)alkyl, hydroxy(1-6C)alkyl (1-6C)alkylamino(1-6C)alkyl, dl-l(1-6C)alkyllamino(1-6C)alkyl, (1-6C)alkylamino(1-6C)-alkoxycarbonyl(l-6C)alkyl, di-l(1-6C)alkylJamino(1-6C)-alkoxycarbonyl(l-6C)alkyl, (1-6C)alkylcarbamoyl(1-6C)alkoxycarbonyl, di-[(1-6C)alkylJcarbamoyl(1-6C)alkoxycarbonyl, carbamoyl-(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkyl~amino(1-6C)alkoxycarbonyl, (1-6C)alkoxy-carbonyl(1-6C)alkanoyl, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, (2-6C)alkynyl(l-6C)alkoxy(l-6C)alkyl, halogeno(l-6C)alkyl-(1-6C)alkoxycarbonyl, phenoxycarbonyl, dl-l(1-6C)alkoxycarbonyllalkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyloxy(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkanoyloxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl-(1-6C)alkyl, hydroxy(1-6C)alkoxy, di-hydroxy(1-6C)alkyl, hydroxy(2-6C)alkenyl, hydoxy(2-6C)alkynyl, (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of sald oxime derivatives; and, in additlon, optlonally bears one or more substituents independently selected from halogeno, hyd~Gx~ amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamlno, di-[(1-6C)alkylJamino N-(1-6C)alkylcarbamoyl, di-N,N-I(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
~ ore particularly, Ar is phenyl ~hich bears one or more substituents independently selected from (1-6C)alkoxycarbonyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkoxyJ(1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl-216~9~
W 0 94/25459 PCTtGB94/00910 (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl-(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio-(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl, phenyl(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxiDe derivatives; and optionally bears one or more further substltuents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-1(1-6C)alkyl~carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxi~e derivatives.
In general, it is preferred that Ar is phenyl Yhich bears one or more substituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl, (1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl and carboxy(1-6C)alkyl; and optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof-and 0-(1-6C)alkyl ethers of said oxime derivatives.
More preferably, Ar is phenyl which bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, 2 1 ~ 0 7 ~ S

_ 9 _ and vhich optionally bears one or more substituents selected from the optional substituents defined in the preceding paragraph. (especially (2-6C)alkenyl such as allyl).
In general, for example, it is preferred that Ar bears one, tvo, three or four substituents.
In particular, X is selected from -C_C-, -CH=CH, -CH2CH2-, -CH20-, -CH2S(O)n- (n.O,l or 2), -CH2NH-, -CH2CO- and -COCH2; more particularly from -C~C-, -CH.CH-, -CH2CH2-, -CH20-, -CH2S- and In general it is preferred, for example, that Rl is hydroxy and R2 is hydrogen.
In general it is preferred, for example, that X ls -C~C-, -CH2CH2-, -CH20 or -CH~CH-, especially -C--C-.
In general, it is preferred, for example, that Ar is phenyl vhich bears one or more (1-6C)alkoxycarbonyl(1-6C)alkyl substituents and vhich, in addition, optionally bears one or more substituents selected from the optional substituents defined above.
Specific values of interest for X include, for example, -C~C-, -CHsCH-, -CH2CH2- and -CH20-.
Specific values for Rl and R2 i~cl~lde, for example, Rl is hydroxy and R is hydrogen.
Specific values for Ar inclllde~ for example, phenyl vhich bears one or more (particularly one or tvo) substituents selected from (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl (such as methoxyethoxycarbonylethyl), (1-6C)alkoxy(1-6C)alkyl (such as methoxypropyl), (1-6C)alkoxycarbonyl(1-6C)alkyl (such as ethoxycarbonylethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, iso-butoxycarbonylethyl, hexyloxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylpentyl), (1-6C)alkoxycarbonyl(1-6C)alkoxy (such as methoxycarbonylmethoxy), (1-6C)alkoxy(1-6C)alkoxy (such as methoxyethoxy), (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl (such as methoxyethoxymethyl, methoxyethoxyethyl), carboxy(1-6C)alkyl (such as carboxyethyl, carboxypropyl), hydroxyalkyl (such as hydroxymethyl), (1-6C)alkanoyl(1-6C)alkyl (such as ethanoylethyl) and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, and 2 1 6 0 7 9 ~

(1-6C)alkoxycarbonyl(1-6C)alkanoyl (such as ethoxycarbonylethanoyl, ethoxycarbonylpropanoyl); and optionally one or more substituents selected from the optional substituents mentioned above and in particular one or tvo substituents selected from (1-6C)alkyl (such as methyl), (2-6C)alkenyl (such as allyl), halogeno (such as fluoro), (1-6C~alkoxy (such as methoxy) and (1-6C)alkanoyl (such as formyl).
Values of Ar of particular interest include those in vhich Ar is phenyl which bears a substituent at the 4-position selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl, (1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl and carboxy(1-6C)alkyl; and vhich optionally bears a substituent at the 2-position selected from the optional substituents defined in the preceding paragraph (especially (2-6C)alkenyl such as allyl).
In one embodiment of the present invention, R1 and R2 are both hydrogen; and ~ and Ar have any of the meanings defined above.
In a further embodiment of the present invention, R1 and R2 are joined together so that CR1-CR2 is a double bond; and ~ and Ar have any of the meanings defined above.
In a further embodiment of the present invention R1 is hydroxy, R2 is hydrogen; and Y and Ar have any of the ~anings defined above.
In a further embodiment there is provided a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or hydroxy;
R2 is hydrogen; or R1 and R2 are joined together so that CR1-CR2 is a double bond;
is selected from -CH2CH2-, -CH=CH-, -C-C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (wherein n is 0,1 or 2);
Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, W O 94/25459 ~ r~ 9 ~ PCT/GB94/00910 (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-1(1-6C)alkyl]a~lno, carbamoyl, (1-6C)alkylcarbamoyl, di-l(1-6C)alkyllcarbamoyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl vhen substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derlvatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl, N-(1-6C)alkylcarba~oyl, N,N-dil(1-6C)alkylcarbamoyl, amino, (1-6C)alkyla~ino, di-~(1-6C)alkyllamino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, cyano, nitro, hydroxy and carboxy;
and wherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, h~d-GXy~ amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedloxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives. provided that vhen X is -OCH2-, -NHCH2- or -S(O)nCH2- (uherein n is 0,1 or 2), then R is not hydroxy.
In a prefered embodiment of the present invention R1 is hydroxy, R is hydrogen, X is selected from -CH2CH2-, -CHsCH-, -C-C-and -CH20- (especially -C_C-); Ar is phenyl which bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(l-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkoxyl(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy, 21607~

(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; and ~herein Ar may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nltro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-1(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
Particular, preferred and specific values include the appropriate values mentioned above.
In a specific embodiment, R1 is hydroxy, R2 is hydrogen ~ is selected from -CH2CH2-, -CH.CH-, -C~C- and -CH20 (especially -C~C-);
Ar is phenyl ~hich bears one or more substituents selected from (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, carboxy(1-6C)alkyl, (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, (1-6C)alkoxycarbonyl(1-6C)alkanoyl; and vherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.

W 0 94125459 216 ~ 7 ~ 5 PCTIGB94/00910 In an embodiment of particular interest R1 is hydroxy, R2 is hydrogen, X ls -C}C-, Ar is phenyl vhich bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, and vhich optlonally bears a further substltuent of (2-6C)alkenyl (such as allyl).
In a further embodiment of the present invention there is provided a compound of formula I (formula set out hereinafter together vith the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, vherein:
R1 is hydrogen or hydroxy;
R2 is hydrogen; or R1 and R2 are ~oined together so that CR -CR is a double bond;
X is selected from -CH2CH2-, -CH~CH-, -C_C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (vherein n is 0,1 or 2);
Ar is phenyl vhich bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-l(1-6C)alkyllamino, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substltuted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-dil(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, and hydroxy;
and vherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; provided that vhen X is -OCH2-, -NHCH2- or -S(O)nCH2- (wherein n is 0,1 or 2), then R1 is not 2;~795 hydroxy; and provided that when a substituent on Ar includes a phenyl moiety, ~ is -OCH2-; then Rl and R2 are not both hydrogen, or ~oined together so that CR -CR is a double bond.
In a further embodiment there is provided a coDpound of formula I (formula set out hereinafter together with the other cheDical formulae referred to herein), or a pharmaceutically acceptable salt thereof, ~herein:
Rl is hydrogen or hydroxy;
R2 is hydrogen; or Rl and R2 are joined together so that CRl-CR2 is a double bond;
X is selected from -CH2CH2-, -CH~CH-, -CoC-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (vherein n is 0,1 or 2);
Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkyla~ino, di-[(1-6C)alkyllamino, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di[(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, and hydroxy;
and wherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; provided that when X is -OCH2-, -NHCH2- or -S(O)nCH2- (~herein n is 0,1 or 2), then R1 is not hydroxy; and provided that when a substituent on Ar includes a phenyl moiety, then ~1 is hydroxy.

W O 94/25459 21~ ~ 7 9 - PCT/GB94/00910 Particular, preferred and specific values include the appropriate values mentioned above.
In particular Ar is phenyl ~hich bears one or oore substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, dl-[(1-6C)alkoxy(1-6C)alkyll(1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxycarbonyl, di-l(1-6C)alkoxyl(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl, di-1(1-6C)alkyllamino(1-6C)alkyl, (1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N- ( 1-6C)alkylcarbaooyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-1(1-6C)alkyllcarbamoyl(1-6C)alkyl;
(1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy, cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy, nitro(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkoxycarbonyl(1-6C)alkylthio;
and, in addition, optionally bears one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbaooyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-~(1-6C)alkyllamino N- ( 1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
Hore particularly, Ar is phenyl ~hich bears one or more substituents independently selected from (1-6C)alkoxycarbonyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-[1-6C)alkoxy(1-6C)alkyll(1-6C)alkoxy, phenyloxy(1-6C)alkoxy, phenyl(1-4C)alkyl and (1-6C)alkoxy(1-6C)alkoxycarbonyl; and optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, W O 94/25459 216 ~ 7 9 ~ PCT/GB94/00910 (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives;
Specific values for Ar include, for example, phenyl vhich bears one or more (particularly one or t~o) substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyl (such as ethoxycarbonyl~ethyl, methoxycarbonylmethyl, ethoxycarbonylethyl), (1-6C)alkoxycarbonyl(1-6C)alkoxy (such as ethoxycarbonylmethoxy), (1-6C)alkoxy(1-6C)alkoxy(such as methoxyethoxy or ethoxyethoxy), di-l1-6C)alkoxy(1-6C)alkyl](1-6C)alkoxy (such as 1-(methoxymethyl)-2-methoxyethoxy), (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl (such as methoxyethoxymethyl), phenoxy(1-6C~alkoxy (such as phenoxyethoxy), (1-6C)alkoxy(1-6C)alkoxycarbonyl (such as methoxyethoxycarbonyl) and benzyl; and optionally one or more (in particular, one or t~o) substituents selected from halogeno (such as chloro), (1-6C)alkanoyla~ino (such as propionamido), (1-6C)alkyl (such as methyl) and (2-6C)alkenyl (such as allyl).
In a further embodiment of the present invention Rl is hydroxy, R2 is hydrogen, ~ is selected from -CH2CH2-, -CH,CH-, -C~C-and -CH20- (especially -C~C-);
Ar is phenyl which bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-[(1-6C)alkoxy(1-6C)alkyl](1-6C)alkoxy, phenyloxy(1-6C)alkoxy, phenyl(1-4C)alkyl and (1-6C)alkoxy(1-6C)alkoxycarbonyl; and Ar optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-1(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, W 0 94/25459 21~ ~ ~ 9 S PCT/GB94/00910 (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
Particular, preferred and specific values include the appropriate values mentioned above.
In a specific embodiment, R1 is hydroxy, R2 is hydrogen ~ is selected from -CH2CH2-, -CH.CH-, -C~C- and -CH20 (especially -CsC-);
~r is phenyl vhich bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyl (such as ethoxycarbonylmethyl, methoxycarbonylmethyl, ethoxycarbonylethyl), (1-6C)alkoxycarbonyl(1-6C)alkoxy (such as ethoxycarbonyl~ethoxy), (1-6C)alkoxy(1-6C)alkoxy(such as methoxyethoxy or ethoxyethoxy), di-[1-6C)alkoxy(1-6C)alkyll(1-6C)alkoxy (such as 1-(methoxymethyl)-2-methoxyethoxy), (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl (such as methoxyethoxymethyl), phenoxy(1-6C)alkoxy (such as phenoxyethoxy), (1-6C)alkoxy(1-6C)alkoxycarbonyl (such as methoxyethoxycarbonyl) and benzyl; and optionally one or more (in particular, one or tYo) substituents selected from halogeno (such as chloro), (1-6C)alkanoylamino (such as propionamido), (1-6C)alkyl (such as methyl) and (2-6C)alkenyl (such as allyl).
In a further embodlment there is provided a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, wherein:
Rl is hydrogen or hydroxy;
R is hydrogen; or R1 and R2 are joined together so that CR1-CR2 is a double bond;
is selected from -CH2CH2-, -CH=CH-, -C-C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2C0-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (wherein n is 0,1 or 2);
Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-1(1-6C)alkyllamino, carbamoyl, (1-6C)alkylcarbamoyl, di-1(1-6C)alkyllcarbamoyl, ~1~0795 (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di[(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;
and vherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carba~oyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl~amino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyl~carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxlme derivatives. provided that when X is -OCH2-, -NHCH2- or -S(O)nCH2- (wherein n is 0,1 or 2), then Rl is not hydroxy; and provided that vhen a substituent on ~r in~ dps a phenyl moiety, X is -OCH2-, then Rl and R2 are not both hydrogen, or ~oined together so that CR -CR is a double bond.
In particular, according to the present invention there is provided a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, wherein:
Rl is hydrogen or hydroxy;
R2 is hydrogen; or R1 and R2 are joined together so that CR1-CR2 is a double bond;
is selected from -CH2CH2-, -CH=CH-, -C-C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2C0-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (wherein n is 0~1 or 2);
Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyllamino, W O 94/25459 216 3 7 ~ 5 PCTIGB94/00910 carbamoyl, (1-6C)alkylcarbamoyl, di-1(1-6C)alkyllcarbamoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl ~hen substituted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di[(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;
and wherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; provided that ~hen X ls -OCH2-, -NHCH2- or -S(O)nCH2- (vherein n is 0,1 or 2), then R1 is not hydroxy; and provided that ~hen a substituent on Ar incl~des a phenyl moiety, then R1 is hydroxy.
Particular, preferred and specific values include the appropriate values mentioned above.
In particular Ar is phenyl vhich bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkoxy(1-6C)alkyll(1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxycarbonyl, di-[(1-6C)alkoxy](1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl, di-l(1-6C)alkyllamino(1-6C)alkyl, (1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl;
(1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, ~16~79~

cyano(1-6C)alkoxy, cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy, nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylthio(l-6C)alkoxy, (1-6C)alkoxy(l-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(l-6C)alkyl, cyano(1-6C)alkyl, carboxy(1-6C)alkyl and hydroxy(1-6C)alkyl; and, in addition, optionally bears one or more substituents independently selected from halogeno, hydroxy, amino, nltro, cyano, carboxy, carbanoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, ~1-6C)alkoxycarbonyl, (1-6C)alkylthlo, (1-6C)alkylsulphlnyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamlno, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of sald oxime derivatlves.
hore particularly, ~r is phenyl ~hich bears one or more substltuents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-~(1-6C)alkoxyl(1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(l-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl, phenyl(1-6C)alkyl, hydroxy(1-6C)alkyl; and optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, W O 94/25459 21~ 3 ~ 3 ~ PCT/GB94/00910 (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
In general, it is preferred that Ar is phenyl vhich bears one or more substituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl and carboxy(1-6C)alkyl; and optionally bears one or more further substituents selected from halogeno, hydroxy, anino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivat-ives.
In a further embodiment there is provided there ls provided a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, vherein:
R1 is hydrogen or hydroxy;
R2 is hydrogen; or R1 and R2 are ~oined together so that CR1-CR2 is a double bond;
is selected from -CH2CH2-, -CH~CH-, -C~C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2C0-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (vherein n is 0,1 or 2);
Ar is phenyl ~hich bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-l(1-6C)alkyllamino, carbamoyl, (1-6C)alkylcarbamoyl, di-l(1-6C)alkyllcarbamoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-dil(1-6C)alkylcarbamoyl, amino, (1-6C)alkylamino, di-~ 6C)alkyllamino, (1-6C)alkoxy, ~ 6~7~

(2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;
and vherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxlme derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives. provided that vhen ~ is -OCH2-, -NHCH2- or -S(O)nCH2- (~herein n is 0,1 or 2), then R1 is not hydroxy; and provided that vhen a substituent on Ar inc1udes a phenyl moiety, ~ is -OCH2-i then R1 and R2 are not both hydrogen, or ~oined together so that CR -CR is a double bond.
In particular, according to the present invention there is provided a compound of formula I (formula set out hereinafter together vith the other chemical formulae referred to herein), or a pharmaceutically acceptable salt thereof, vherein:
R1 is hydrogen or hydroxy;
R2 is hydrogen; or Rl and R2 are joined together so that CR1-CR2 is a double bond;
X is selected from -CH2CH2-, -CH-CH-, -C~C-, -CH20-, -OCH2-, -CH2NH-, -NHCH2-, -CH2C0-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (vherein n is 0,1 or 2);
Ar is phenyl vhich bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyllamino, carbamoyl, (1-6C)alkylcarbamoyl, di-1(1-6C)alkyllcarbamoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl vhen substituted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino, W O 94/25459 216 0 ~ g 5 PCT/GB94/00910 (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-dil(1-6C)alkylcarbamoyl, amino, (1-6C)alkylamino, di-l(1-6C)alkyllamino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;
and ~herein ~r and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-1(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; provided that Yhen X is -OCH2-, -NHCH2- or -S(O)nCH2- (vherein n is 0,1 or 2), then R is not hydroxy; and provided that ~hen a substituent on Ar ~nrlud~5 a phenyl moiety, then R1 is hydroxy.
In particular Ar is phenyl ~hich bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkoxy(1-6C)alkyll(1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxycarbonyl, di-l(1-6C)alkoxyl(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl, di-l(1-6C)alkyllamino(1-6C)alkyl, (1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-1(1-6C)alkyllcarbamoyl(1-6C)alkyl;
(1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy, cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy, nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, w716073~

(1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkyl, carboxy(1-6C)alkyl, hydroxy(1-6C)alkyl (1-6C)alkylamino(1-6C)alkyl, di-[(1-6C)alkyllamino(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkoxycarbonyl(1-6C)alkyl, dl-l(1-6C)alkyl~amlno(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylcarbamoyl(1-6C)alkoxycarbonyl, di-1(1-6C)alkyllcarbamoyl-(1-6C)alkoxycarbonyl, carbamoyl(1-6C)alkoxycarbonyl, (1-6C)alkoxy-carbonyl(1-6C)alkoxy(l-6C)alkyl, di-l(1-6C)alkyl]amino(1-6C)-alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, (2-6C)alkynyl(1-6C)alkoxy-(1-6C)alkyl, halogeno(1-6C)alkyl(1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; and, in addltlon, optionally bears one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, dl-1(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, dl-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphlnyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
Hore particularly, Ar ls phenyl whlch bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-l(1-6C)alkoxy](1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl, W O 94/25459 21~ PCT/GB94/00910 phenyl(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; and optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-l(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
In general, it is preferred that Ar is phenyl ~hich bears one or more substituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl, (1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl, and carboxy(1-6C)alkyl; and optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-1(1-6C)alkyllamino N-(1-6C)alkylcarbamoyl, di-N,N-l(1-6C)alkyllcarbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.
Compounds of the invention ~hich are of particular interest include the compounds described in the accompanying Examples (and their pharmaceutically-acceptable salts), and are hence provided as a further feature of the present invention. In particular, the present invention provides a compound as described in Example 1, 23, 26, 27, 28, 30, 35, 44, 55, 65, 66, 67, 68, 69, 83, 84, 85, 115 and 120 and their pharmaceutically acceptable salts.

W 0 94/2s4~ 1 6 0 7 ~ ~

A suitable pharmaceutically-acceptable salt of the present invention comprises an acid-addition salt derived from an inorganic or organic acid vhich provides a pharmaceutically-acceptable anion.
Thus, examples of salts of the present invention include acid-addition salts with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, trifluoroacetic, citric, tartaric, succinic, maleic, fumaric or acetic acid. In addltion, suitable pharmaceuticaIly-acceptable salts include Ivhere the compound of formula I is sufficiently acidic, for example where the compound of formula I bears an acidic substituent such as carboxyl those formed vith a base vhich affords a pharmaceutically acceptable cation. Suitable bases include an alkali metal salt (such as a sodium or potassium salt), an ~ line earth metal salt (such as a calcium or magnesium salt), an ammonium salt or a salt with an organic base vhich affords a physiologically-acceptable cation such as a salt with methylamine, dimethylamine, triethylamine, piperidine or morpholine.
The compounds of the present invention may be obtained by standard procedures of organic chemistry already known to be applicable to the preparation of structurally analogous compounds.
Such procedures for the preparation of the compounds of formula I, or pharmaceutically acceptable salts thereof, are provided as a further feature of the present invention and are illustrated by the follo~ing preferred processes in which the various generic radicals, for example, R1, R2, ~ and Ar may take any of the _~nings hereinbefore defined.
Thus, according to the present invention there is also provided a process for preparing a compound of formula I, or a pharmaceutically-acceptable salt thereof, which process comprises:

(a) For those compounds of formula I in which Rl and R2 are both hydrogen, reducing a compound of formula I in which Rl and R2 are joined together so that CR1-CR2 is a double bond.
The reduction may be carried out, for example, by catalytic hydrogenation, or by reaction with a suitable reducing agent.
Suitable reaction conditions include, for example, catalytic hydrogenation using a catalyst which comprises a noble metal.

W O 94/25459 216 ~ rJ 3 r PCT/GB94/00910 Particular catalysts include palladium, platinum and nickel (especially when in the finely divided state knovn as raney nickel), and catalysts in vhich the noble metal is supported on an inert carrier such as carbon. A specific example of a supported catalyst is Pd/C. The reduction is conveniently carried out in a solvent of, for example, an alcohol (such as ethanol), and at (or near) a~bient temperature and optionally under pressure.
Further suitable reaction conditions include, for example, reduction with a borane such as diborane. The reaction ls generally carried out in an inert solvent of, for example, tetrahydrofuran or methyl t-butyl ether at, for example, 0-60C. It may be preferable to cool the reaction belov ambient temperature (eg. to about 0C) during the reduction. The borane generated may be hydrolysed by treatment vith an organic acid such as acetic acid, vhich hydrolysis may be carried out at 0-60C, and may be accelerated by heating (eg.
refluxing).

(b) For compounds of formula I in vhich R1 and R2 are ~oined together so that CRl-CR2 is a double bond, dehydrating a compound of formula I in vhich R1 is hydroxy and R2 is hydrogen.

The dehydration may be carried out using an acid such as sulphuric acid (eg. concentrated sulphuric acid), or ~-toluene sulphonic acid. The reaction is conveniently carried out vith heating, and conveniently an inert solvent is employed. For example, the reaction may be carried out using sulphuric acid at temperatures of about 70-130C; or using p-toluene sulphonic acid in a hydrocarbon solvent of, for example, toluene or xylene at ambient temperature to reflux, and preferably at reflux. The dehydration may also be carried out using trifluoroacetic acid in an inert solvent such as dichloromethane (at ambient temperature to reflux temperature).

(c) For compounds of formula I in which R1 and R2 are joined together so that CR1-CR2 is a double bond, treating a compound of formula II in which Z is a leaving group with a base.
Suitable values for Z include, for example, halogen such as 216~7~

chloro, bromo, iodo, or a methylsulphonyloxy or toluenesulphonyloxy group. Sultable bases include hydroxide (such as potassium or sodium hydroxide), and alkoxide (such as potassium t-butoxide or sodium ethoxide).
The reaction is conveniently carried out in the presence of a solvent, preferably a polar organic solvent. Sultable solvents include, for example, an alcohol (such as ethanol), or an aprotic solvent such as dimethylformamide or N-methylpyrrolidone. The reaction may be carried out at ambient temperature or at an elevated temperature, such as at a temperature betveen ambient and the reflux temperature of the reaction mixture. This method is generally preferred over that described in (b) when X is -OCH2- or -SCH2-.
The compounds of formula II may be prepared from a compound of formula I in vhich R1 is hydroxy. For example, where Z is halogen the compound of formula I in ~hich Rl is hydroxy and R2 is hydrogen may be reacted with the appropriate phosphorous halide (eg. PC15, PBr3 or PI3), or where Z is chloro, by reaction ~ith thionyl chloride. The compound of formula I in ~hich Rl is hydroxy may be reacted vith mesyl chloride to the compound in Yhich Z is methylsulphonyloxy; and ~ith tosyl chloride to give Z is toluene sulphonyloxy.

(d) For those compounds of formula I in which ~ is -CH2CO-, reacting an organometallic compound of formula III in which h is a metal atom or a derivative thereof, with a compound of formula IV.
Suitable values for ~ include, for example, magnesium and lithium. In the case ~here h is magnesium it is conveniently present in the form of a derivative of formula -hgX where ~ is a halogen atom such as iodo or bromo, so that the organometallic compound of formula III is in the form known as a Grignard Reagent. The reaction is generally carried out in an inert solvent such as dry diethyl ether or tetrahydrofuran. For example, the reaction may be carried out at a temperature between 0C and the reflux temperature of the reaction mixture.

W O 94/25459 21 fi ~ 7 ~ ~ PCT/GB94/00910 The compounds of formula III may be prepared from the corresponding compound of formula Ar-nhal" in uhich "hal~ is a halogen atom, such as iodo or bromo as is uell known in the art.

e) For those compounds of formula I in uhich X is -CH2-NH- or -NHCH2-, reducing a compound of formula I in which X is -CH-N- or -N,CH- (as appropriate).
The reaction may be carried out using a chemical reducing agent such as a hydride in a solvent such as an alcohol at ambient temperature. Thus, in a particular example, the reduction may be carried out using sodium borohydride in a solvent such as methanol at a~bient temperature. The reduction may also be carried out by selective catalytic hydrogenation using similar conditions to those described under (a) above.
It Yill be appreciated that the preferred method of reduction Yill depend upon the value of g. Thus, for example, where debenzylation is possible (eg. uhen g is -NHCH2-), it is generally preferred that a chemical reducing agent is employed.
The compounds of formula I in which g is -CH-N- may be prepared by reaction of a compound of formula V vith a compound of formula VI. The reaction is generally carried out in an inert hydrocarbon solvent such as toluene or benzene, Yith heatlng (eg. at reflux) and the reaction may be accelerated by removing Yater generated in the reaction by azeotropic distillation. Similarly, the compounds of formula I in which X is -N.CH- may be prepared by reaction of a compound of formula VII Yith a compound of formula VIII.

f) For those compounds of formula I in which X is -CH2NH-, -CH20-, -CH2S-, Rl is hydroxy and R2 is hydrogen, reacting a compound of formula IX in uhich Z is -NH2, -OH or SH as appropriate uith a compound of formula X.
The reaction is conveniently carried out in a solvent such an inert hydrocarbon eg. toluene with heating. The reaction may be facilitated by the presence of acid or base.
The compound of formula X is conveniently generated in situ, by, for example, treating quinuclidin-3-one with trimethylsulphoxonium 21607~
W 0 9412~459 PCT/GB94/00910 iodide in the presence of a base of, for example, an alkali metal hydride such as sodium hydride and in a solvent such as dimethylformamide, or an alkali metal hydroxide such as sodium hydroxide in a solvent such as an aqueous solvent.
The compound of formula X may also be prepared from a ~halohydrin" as is vell known in the art. The halohydrin may be prepared, for example, by addition of HOCl to the correspondlng olefin and the halohydrin treated with base (eg. NaOH) to give the compound of formula ~.

g) For compounds of formula I in which X is -CH.CH-, reacting a compound of formula ~I with a compound of formula V in the presence of a base.
Suitable bases include alkoxides, such as potassium t-butoxide, and the reaction is conveniently carried out in an inert solvent such as tetrahydrofuran with cooling below ambient temperature eg -40C to 0C); and metal hydrides such as sodium hydride in a solvent such as dimethyl formamide or dimethyl suphoxide. A
particularly suitable base is, for example, sodium dimsyl which may conveniently be used in a solvent such as dimethyl sulphoxide.
The compounds of formula ~I may be prepared by reaction of a compound of formula ArCH2-hal in which "hal~ is halogen, such as chloro, with triphenylphosphine as is well known in the art.

h) For those compounds of formula I in which ~ is -CH2CH2-, reducing a compound of formula I in which ~ is -CH~CH- or in which X
is _CEC_ .
The reaction may conveniently be carried out by catalytic hydrogenation using conditions similar to those mentioned in (a) above.
In an alternative synthesis a compound of formula ArCH2CH2-hal vherein "hal" represents a halogen atom such as bromo, is reacted with quinuclidin-3-one in the presence of sec-butyl lithium, with cooling (eg -70C) in an inert solvent such as tetrahydrofuran.

W O 94/25459 2 1 ~ PCT/GB94/00910 i) For compounds of formula I in which X is -COCH2-, reacting a compound of formula ~II in ~hich h is a metal atom or a derivative thereof, vith a compound of formula ~III.
Suitable values for h and suitable reaction condltions are those mentioned in (d) above. The compounds of formula ~II may be prepared from the corresponding halogeno compound in a manner analogous to the preparation of compounds of formula III discussed in (d) above.

;) For those compounds of formula I in which X is -CH20- or -CH2S-, reacting a compound of formula XIV vith a compound of formula ~V, in vhich zl is a leaving group and z2 is -Y~, or zl is -Y~ and z2 is a leaving group, and ~herein Y is oxygen or sulphur (as appropriate) and h is a metal atom.
Suitable leaving groups include, for example, halogen (such as chloro, bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy or trlfluoromethanesulphonyloxy; and suitable metals include, for example sodium and lithium.
The process is generally performed in the presence of a suitable solvent, for example, a hydrocarbon, such as toluene or xylene, or an ether such as dioxan or tetrahydrofuran, and at a temperature in the range, for example 20-150C.
It may be desirable to protect the qllinuclidine nitrogen atom during the reaction, especially vhen z1 is -Y~, as described in (l) belo~. It may be desirable to protect R1 ~hen it represents a hydroxy group as, for example, a silyl ether.

k) For those compounds of formula I in ~hich ~ is -OCH2- or -SCH2- and R1 and R2 are both hydrogen, reacting a compound of formula ~VI in ~hich Y is oxygen or sulphur as appropriate ~ith a compound of formula ~VII in ~hich Z is a leaving group.
Suitable leaving groups include halogen, such as chloro, bromo or iodo, methanesulphonyloxy and toluenesulphonyloxy. The reaction is generally carried out in the presence of a base such as an alkali metal hydroxide, eg sodium or potassium hydroxide, and in a solvent such as dimethyl sulphoxide or dimethylformamide.

Wo 94/25459 21~ ~ 7 3 S PCT/GB94/00910 1) For compounds of formula I in which X is -OCH2-, -SCH2-, -CH20-, or -CH2S-, deprotecting a compound of formula XVIII in which Q
is a protecting group.
Suitable values for Q include, for example, -BH3 or an oxygen atom. Vhen Q is -BH3 the deprotection may be carried out by treatment with an acid such as hydrochloric acid in acetone. ~hen Q
is an oxygen atom deprotection may be carried out by reduction using a suitable reducing agent such as sulphur dioxide.
The compounds of formula XYIII in which X is -CH20- or -CH2S- may be prepared by methods analogous to those described in (;), and in which X is -OCH2- or -SCH2- by methods analogous to those described in (k) above, but in which the starting material containing the quinuclidine moiety is protected by Q. A preferred vay of preparing compounds of formula XVIII in vhich X is -CH20- or -CH2S-and R1 is hydroxy and R is hydrogen is by a procedure analogous to that described in (f) in which the compound of formula X is protected by Q. The quinuclidine moiety in the various starting materials may be protected using methodology well known in the art. Thus, for example, those in which Q is BH3 may be prepared by reaction of the appropriate quinuclidine moiety with BH3.THF, generally with cooling (for example at -70C); whilst those in which Q is an oxygen atom may be prepared by oxidation of the appropriate quinuclidine moiety with, for example, 30Z hydrogen peroxide.

m) For those compounds of formula I in ~hich X is -C~C-, reacting a compound of formula I in which X is -CH=CH- with a halogen, folloved by treatment with a base.
A suitable halogen is bromine and the reaction is conveniently carried out in an inert solvent such as carbon tetrachloride. Suitable bases include, for example, potasium t-butoxide. This treatment is conveniently carried out in a solvent such as THF, with heating (eg. at a temperature between ambient and about 70C).

WO 94/25459 ~16 0 7 ~ i~ PCT/GB94/00910 n) For those compounds of formula I in vhich R1 is hydroxy, R2 is hydrogen and X is -C_C-, reacting a compound of formula XIX in Yhich ~ is a metal atom, with quinuclidin-3-one.
A suitable metal is llthium and suitable reaction conditions include those mentioned in (d) above.

o) For those compounds in vhich R1 and R2 are hydrogen and X is -C-C-, reacting a compound of formula XI~ in vhich h is a metal atom vith a compound of for~ula XV in vhich Z is a leaving group.
Suitable values for Z include, for example, halogen (such as chloro, bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy or trlfluoromethanesulphonyloxy; suitable values for h include, for example, lithlum; and suitable reaction conditions include those mentioned under (d) above.

p) For those compounds in vhich ~ is -C-C- and R1 is hydrogen or hydroxy and R2 is hydrogen, reacting a compound of formula XX vith a compound of formula IX in vhich Z is a leaving group in the presence of a catalyst.
Sultable catalysts include, for example, transitlon metal complexes such as palladium or nickel complexes. Particular catalysts are palladium (II) complexes, a specific example of vhich is Pd(PPh3)2Cl2. Suitable values for Z include, for example, halogen (such as chloro, bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy and trifluoromethanesulphonyloxy. The reaction is generally carried out in the presence of a base, for example, an amine such as triethylamine and in a solvent such as dimethylformamide vith heating (for example at 60 to 100C). The reaction is preferably carried out in the prersence of copper(I)iodide. Compounds of formula XX may be prepared according to Scheme la and 2b.

q) For those compounds in vhich ~ is -C=C- and Rl is hydrogen or hydroxy and R2 is hydrogen, reacting a compound of formula XXI vith a compound of formula IX in which Z is a leaving group in the presence of a catalyst.

Suitable reaction conditions are those mentioned under (p) above. Compounds of formula ~I may be prepared according to Scheme lb and 2a.

r) For those compounds in which X is -CH=CH-, reducing a compound of formula I in which ~ is -CzC-.
The reaction may be carried out by catalytic hydrogenation using conditions similar to those mentioned in (a) above. A
particularly suitable catalyst is, for example, l~ndl~rs catalyst (Pd on BaS04 poisoned with quinoline). The reaction may also be carried out using a reducing agent such as trhose mentioned under (a) above or lithium aluminium hydride in a suitable solvent such as diethylether at ambient temperature or ~ith cooling.

s) For those compounds of formula I in which ~ is -CHzCH-, reacting a compound of formula XXII in which L is a suitable ligand with a compound of formula IX in which Z ls a leaving group in the presence of a catalyst.
Suitable values for L include, for example, (1-6C)alkyl with butyl being preferred. Suitable values for Z, suitable catalysts and reaction conditions include those mentioned under (p) above. A
particularly suitable catalyst is, for example, tris(dibenzylidine acetone)palladium lOl.
The compounds of fonmula I in vhich ~ is -SCH2- may be be oxidised to these in which the sulphur atom bears an oxygen atom (that is to a "sulphoxiden) using, for example an appropriate quantity of sodium periodate. Further oxidation to the compound in which the sulphur atom bears two oxygen atoms (that is a "sulphone") may be carried out using a peracid such as peracetic acid or hydrogen peroxide. The oxidation of sulphur compounds to the corresponding sulphoxides and sulphones is well kno~n in the chemical art.
Compounds of formula I in which X is -CH2S- may be oxidised to the corresponding sulphoxides or sulphones in the same way.
In some cases oxidation of compounds of formula I to give a sulphone may be accompanied by some oxidation of the nitrogen atom in the quinuclidine ring to the N-oxide. In such cases the quinuclidine WO 94/25459 2 1 6 ~ ~ ~ 5 PCT/GB94/00910 N-oxide moiety may be reduced back to a quinuclidine moiety ~ithout affecting the sulphone using reducing agents well knoYn in the art, such as sulphur dioxide.
It vill be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensltive groups in the compounds. The instances vhere protection is necessary or desirable and suitable methods for protection are knoYn to those skilled in the art. Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. Suitable protecting groups for hydroxy include, for example, silyl groups such as trimethylsilyl or t-butyldimethylsilyl, tetrahydropyranyl and esterifing groups such as a methyl or ethyl ester; and for amino groups incllJde benzyloxycarbonyl and t-butoxycarbonyl. Carboxy groups may be protected in a reduced form such as in the form of the corresponding protected alcohol, ~hich may be subsequently oxidised to give the carboxy group. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques ~ell knoYn in the chemical art.
It ~ill also be appreciated that the preferred process for preparing a particular compound of formula I ~ill depend upon the nature of the various radicals. Similarly, the preferred choice of reagent ~ill depend upon the nature of the various radicals present.
For example, vhen it is required to reduce a particular compound the reducing agent ~ill generally be selected to be one vhich does not interfere with other groupings present.
It ~ill also be appreciated that certain of the various optional substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are ~ell known in 21~07~
W O 94/254~9 the chemical art. Particular examples of aromatic substitutlon reactions include the introductlon of a nitro group using concentrated nitric acid, the introductlon of an acyl group using, for exanple, an acylhalide and Levis acid (such as aluminium trichloride) under Frledel Crafts conditlons; the introduction of an alkyl group using an alkyl halide and Le~is acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
Particular exaoples of modiflcations include the reductlon of a nitro group to an anino group by for example, catalytic hydrogenation with a nickel catalyst or treatment vith iron in the presence of hydrochloric acid vith heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will be appreciated that the substituents on ~r may be reacted, using standard chemlcal methodology, to produce further groups. Thus, for example, ester groups may be hydrolysed to acid groups which may be reduced to give a hydroxy group. The hydroxy group may then be reacted ~ith further reagents to give further groups.
In general, it is preferred that the substituents on Ar are introduced before Ar is coupled to the quinuclidine moiety but in some instances it may be appropriate to introduce substituents or modifiy substituents after such coupling. The various substituted phenyl derivatives used as starting materials may, as indicated above, be prepared by methods well known in the art. As particular examples starting materials in which Ar bears an alkoxy group which may be further substitututed as defined above may be prepared by alkylation of the appropriate phenol. Thus a compound of formula Hal-Ar-OH may be reacted ~ith a compound of formula R-hal in the presence of a base and a suitable solvent (Hal are suitable halogen atoms and R
represents .~ ~inder of the substituent to be introduced, thus, for example R will be alkoxyalkyl when an alkoxyalkoxy substituent is desired . Specific examples illustrating the generation of alkoxy substituents further substituted by other groups are sho~n in Scheme 3. Compounds in which Ar bears an alkylthio group which may be further substituted may be prepared in an analogous manner. Compounds in which Ar bears an alkoxycarbonylalkyl group may be prepared by W O 94/254~9 ~ 1 6 Q r~ ~ ~ PCT/GB94/00910 esterification of a compound bearing a carboxyalkyl group using the appropriate alcohol and standard conditions such as acid catalysis (eg. sulphuric acid). An alkynyl group (which may be further substituted as defined above) may be introduced, for example, by reaction of an appropriate compound of formula Ar-Z in ~hich Z is a suit~ble leaving group vith a compound of formula HC_C-R in ~hich R
represents the remainder of the substituent in a similar manner to that described in (p) above. In a similar manner compounds ~ith an alkenyl substiuent (which may be further substituted) may be prepared from a compound of formula Ar-Z and R-CH.CH2. Compounds having an alkenyl substituent such as allyl and an oxy substituent may be prepared from a compound of formula ArOH by reaction ~ith, for example, allyl bromide follo~ed by a Claisen rearrangement as illustrated in Scheme 3.
Compounds in vhich Ar bears a (CH2)nCO2R group in vhich n is 1 or greater than 1 and R is, for example, alkyl may be prepared, for example, by a Yittig reaction on the corresponding compound of formula Ar(CH2)mCORl1 (m . n - 1, R11 , H or alkyl) as illustrated in Scheme 4. The product may then be further modified using stand reaction conditons to provide further desired groups eg. hydrolysed to the acid. Compounds having a (CH2)nCO2R group may also be prepared from compounds of formula Ar(CH2)mCHO (m ~ n - 1) as illustrated in Scheme 4. The acids provided may then be further modified by, for example, reduction or esterification to provide further groups or groups which can be reacted further.
~ hen a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound ~ith the appropriate acid (~hich affords a physiologically acceptable anion), or vith the appropriate base (which affords a physiologically acceptable cation), or by any other conventional salt formation procedure.
As mentioned previously, the compounds of the formula I (and their pharmaceutically-acceptable salts) are inhibitors of the enzyme squalene synthase. Thus the compounds of the present invention are capable of inhibiting cholesterol biosynthesis by inhibition of de novo squalene production.

21~37~

The beneficial pharmacological properties of the compounds of the present invention may be demonstrated using one or more of the following techniques.

(a) Inhibition of Squalene synthase In this test, the ability of a compound to prevent the formation of squalene from a radioactive substrate (tritiated farnesyl pyrophosphate) is assessed.
The test compound is incubated at a concentration of 25 micromolar in 200~1 of a buffered solution containing potassium phosphate (50mh), hgCl2 (4.95mh), ~F (9.9mh), NADPH (0.9mh) and rat liver microsomal protein (20~g). Rat liver microsomes are prepared by the method described in published European Patent Application No. 324,421 and stored in liquid nitrogen prior to assay. Assay vials are kept at 37C
throughout the incubation.
The reaction is started ~ith the addition of the substrate ~ 3HI-farnesyl pyrophosphate), final concentration 20~h, and stopped after 15 minutes reaction time vith the addition of 50~1 of 4X KOH. The reaction products are separated from unreacted substrate after application to a C-18 octadecyl lccBond column (Analytichem Int product No. 617101). An aqueous fraction is eluted with 250~1 of 0.1h KOH.
Squalene is then eluted ~ith 1.0 ml 10X ethylacetate in hexane and radioactlvity determined. The difference in radioactivity in the presence and absence of the test compound is used to determine the level of inhibition. If the test compound inhibits at greater than about 70Z
at 25 micromolar, it is generally re-tested at 25 and 2.5 micromolar.
The IC50 (concentration which results in a 50X inhibition of squalene production), of the test compound can be determined by testing the compound at several, for example five, concentrations predicted from the t~o concentration results. The IC50 can then be determined from a plot of percentage inhibition against concentration of test compound.
In general, compounds of formula I show significant inhibition in the above test at a concentration in the range of about 0.001 to 25~h.
~ y way of illustration of the squalene synthase inhibitory properties of the compound of formula I, described in Example 16 below gave an inhibition of about 80X at 2.5~.

WO 94/25459 ~1 rl r 9 ~ PCT/GB94/00910 (b) Acute rat cholesterol synthesis assay.
Thls is an acute in vivo test in the rat to measure de novo hepatic cholesterol synthesis from exogenously administered 14C-acetate.
Yemale rats (35 - 55 g) are housed in reverse lighting condltions (red light fron 0200h - 1400h) for a period of about 2 Yeeks prior to test. ~n~ ~15 are alloved free access to chov and drinking vater throughout this period. At test, animals should Yeigh 125 - 150 g.
Test compounds may be administered by oral gavage, dissolved or suspended in 0.5Z polysorbate, or by ip or iv dosing. Control animals receive vehlcle alone. After 1 hour the rats are in~ected ip vith 25~Ci 12-1 C]-acetate (NEN DUPONT. specific activity, 45-60mCi/mnol NEC-085H, or ~FRSHA~ specific activlty, 50-60mCi/mmol CFA 14) in a volume of 0.25 ml saline (100~Ci/ml). After a further hour, rats are terminally anaesthetised Yith halothane and a blood sample obtained from the abdominal vena cava.
1ml of plasma is lyophilised and then saponified in 2ml ethanolic KOH (1 part 33Z KOH, 9 parts ethanol) at 75C for 2 hours.
After addition of an equal quantity of vater, non-saponifiable lipids are extracted Yith tvo Sml volumes of hexane. The hexane extracts are evaporated to dryness and the residues dissolved in ethanol to determine cholesterol specific radioactivity. ED50 values can be determined in the standard Yay.
In general, compounds of formula I shoY activity in the range of about 0.1 to 100 mg/kg.
By vay of illustration, the compound of formula I described in Example 16 gave an ED50 of about 5.lmg/kg.
No overt toxicity vas detected Yhen compounds of the formula I
vere administered at several multiples of their minimum inhibitory dose or concentration.
An alternative test to measure the ability of a compound to inhibit cholesterol synthesis in vivo uses 3H-mevalonolactone in place of 4c-acetate-As mentioned above, the compounds of the present invention are squalene synthase inhibitors and hence possess the property of inhibiting cholesterol biosynthesis. Thus the compounds of the present invention 216079~

uill be useful in treating diseases or medical conditions in uhich an inhibition of squalene synthase is desirable, for example those in vhich a lovering of the level of cholesterol is blood plasma is desirable. In particular, the compounds of the present invention vill be useful in treating hypercholesterolemia and/or ischaemic diseases associated vith atheromatous vascular degeneration such as atherosclerosis. The compounds of the present invention vill also be useful in treating fungal infections.
Thus according to a further feature of the present invention there is provided a method of inhibiting squalene synthase in a varm-blooded animals (such as man) requiring such treatment, vhich method comprises administering to said animal an effective amount of a compound of formula I (as herein defined), or a pharmaceutically-acceptable salt thereof. In particular, the present invention provides a method of inhibiting cholesterol biosynthesis, and more particularly to a method of treating hypercholesterolemia and atheromatous vascular degeneration (such as atherosclerosis).
Thus the present invention also provides the use of a compound of formula I (as herein defined), or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for treating diseases or medical conditions in vhich a lovering of the level of cholesterol in blood plasma is desirable (such as hypercholesterolemia and atherosclerosis).
Uhen used in the treatment of diseases and medical conditions in vhich an inhibition of cholesterol biosynthesis is desired, for example in the treatment of hypercholesterolemia or atherosclerosis, it is envisaged that a compound of formula I (or a pharmaceutically acceptable salt thereof) vill be administered orally, intravenously, or by some other medically acceptable route so that a dose in the general range of, for example, 0.01 to 50 mg per kg body ueight is received.
Houever it vill be understood that the precise dose administered vill necessarily vary according to the nature and severity of the disease, the age and sex of the patient being treated and the route of administration.
In general, the compounds of formula I (or a pharmaceutically-acceptable salt thereof) will usually be administered in the form of a pharmaceutical composition, that is together uith a WO 94/2~459 2 1 ~

pharmaceutically acceptable diluent or carrier, and such a composition is provided as a further feature of the present invention.
A pharmaceutical composition of the present invention may be in a variety of dosage forms. For example, it may be in the form of tablets, capsules, solutions or suspensions for oral administration, in the form of a suppository for rectal administration; in the form of a sterile solution or suspension for parenteral administration such as by intravenous or intramuscular in;ection.
A composition may be obtained by conventional procedures using pharmaceutically acceptable diluents and carriers Yell knovn in the art.
Tablets and capsules for oral administration may conveniently be formed Yith a coating, such as an enteric coating (for example, one based on cellulose acetate phthalate), to ~ini-ise dissolution of the active ingredient of formula I (or a pharmaceutically-acceptable salt thereof) in the stomach or to mask unpleasant taste.
The compounds of the present invention may, if desired, be administered together Yith (or sequentially to) one or more other phanmacological agents knovn to be useful in the treatment of cardiovascular disease, for example, together vith agents such as H~G-CoA
reductase inhibitors, bile acid sequestrants, other hypocholesterolaemic agents such as flbrates, for example gemfibrozil, and drugs for the treatment of coronary heart disease. As a further example, the compounds of the present invention may, if desired, be administered together vith (or sequentially to) an angiotensin converting enzyme (ACE) inhibitor, such as captopril, lisinopril, zofenopril or enalapril.
The invention Yill now be illustrated by the folloving non-limiting Examples in ~hich, unless othervise stated:-(i) evaporations Yere carried out by rotary evaporation in vacuo;
(ii) operations vere carried out at room temperature, that is in the range 18-26C;
(iii) flash column chromatography or medium pressure liquid chromatography (HPLC) Yas performed on silica gel (nerck Kieselgel Art.9385, obtained from E ~erck, Darmstadt, Germany);
(iv) yields are given for illustration only and are not necessarily the maximum attainable by diligent process development;

21~079S
W O 94l25459 PCT/GB94/00910 (v) proton NHR spectra vere normally determined at 200 HHz in DHSO-d6 (unless stated otherwise) using tetramethylsilane (THS) as an internal standard, and are expressed as chemical shifts (delta values) ln parts per million relative to TnS using conventional abbre~iations for designation of ma~or peaks: s, singlet; m, multiplet; t, triplet; br, broad; d, doublet;
(vi) all end-products vere characterised by microanalysis, NHR
and/or mass spectroscopy (molecular ions denoted by m/z values); and (vii) conventional abbreviations are used for individual radicals and recrystallisation solvents, for example, He , methyl, Et =
ethyl, Pr = Propyl, pri = isopropyl, Bu . butyl, ~ui c isobutyl, Ph - phenyl; EtOAc - ethyl acetate, Et2O . ether, HeCN . acetonitrile, heOH = methanol, EtOH . ethanol, PrlOH =
2-propanol, H2O ~ water.

E~PL~ 1 Bis(triphenylphosphlne)-pall~dium (II) chlorlde (85 mg) and copper (I) iodide (43 mg) were added to a solution of ethyl 3-(3-allyl-4-trlfluoromethylsulphonyloxyphenyl)proplonate (920 mg) and 3-ethynyl-3-hydroxyquinuclidine (375 mg) in dimethyl formamide (5 ml) at ambient temperature under an atmosphere of argon. Trlethylamine (2.5 ml) was added. The mixture was then stlrred for 6 hours at 75C.
The reaction mixture was cooled to amblent temperature.
~ater (50 ml) and 2h aqueous sodlum carbonate solutlon (25 ml) vere added to the mixture and the aqueous phase was extracted with ethyl acetate (3x25 ml). The organic phase was filtered. The filtrate was washed vith 2H aqueous sodium carbonate solution (1x25 ml) and then with saturated brine solution (1x50 ml). The organic phase was dried (hgSO4) and evaporated to give an oil which was purified by column chromatography on alumina (Alumina 507 C) using a 19:1 (v/v) mixture of ethyl acetate and methanol as eluent to give an oil. The oil was triturated with hexane to give 3-[2-{2-allyl-4-(2-ethoxy-carbonylethyl)-phenyl~ethynyl]quinuclidin-3-ol as a solid (270 mg), m.p. 55-6 C; microanalysis, found: C, 74.6; H, 8.1; N, 3.70Z, C23H29N03Ø1 H20 requires: C, 74.8; H, 8.0; N, 3.80%; NHR (CDC13):

W O 94/25459 21 6 ~ ~ 9 ~ PCT/GB94/00910 _ 43 -1.22 (3H, t), 1.35-1.50 (lH, m), 1.58-1.80 (lH, m), 1.90-2.13 (3H, m), 2.38-2.57 (lH, m), 2.58 (2H, t), 2.72-2.95 (6H, m), 3.05 (lH, d), 3.30 (lH, d of d), 3.49 (2H, d), 4.12 (2H, q), 4.98-5.10 (2H, m), 5.85-6.03 (lH, m), 6.98-7.07 (2H, m) and 7.33 (lH, d); m/z 368 (H+H).
The ethyl 3-(3-allyl 4-trifluoromethylsulphonyloxyphenyl)-propionate used as starting material vas obtained as follovs.
Allyl bromide (2.30 g) vas added to a stirred suspension of ethyl 3-(4-hydroxyphenyl)propionate (3.49 g) and anhydrous potassium carbonate (2.76 g) in butan-2-one (30ml). The reaction mixture vas heated at reflux for 18 hours. The reaction mixture vas allowed to cool to ambient temperature and the mixture ~as filtered. The filtrate vas evaporated to give an oil vhich was purified by column chromatography on sil~ca gel (nerck ~rt. No. 9385) using a 4:1 (v/v) mixture of n-hexane and ethyl acetate as eluent to give ethyl 3-(4-allyloxyphenyl)propionate (4.09 g) as a colourless oil; N~R (CDC13):
1.22 (3H, t), 2.48 (2H, t), 2.88 (2H, t), 4.13 (2H, q), 4.51 (2H, m), 5.2S-5.42 (2H, m), 5.95-6.15 (lH, m), 6.83 (2H, d) and 7.03 (2H, d);
m/z 235 (~+H).
A solution of ethyl 3-(4-allyloxyphenyl)propionate (3 g) in diphenyl ether (24 ml) vas heated at reflux for 12 minutes. The reaction mixture vas alloved to cool to ambient temperature and the reaction mixture vas filtered through a silica gel pad. Elution vith a 4:1 (v/v) mixture of hexane and ethyl acetate gave slightly impure product. Further purification by medium pressure column chromatography on silica gel (Herck Art. No. 9385) using a 9:1 (v/v) mixture of n-hexane and ethyl acetate as eluent gave ethyl (3-allyl-4-hydroxyphenyl)propionate (2.86 g) as a yellov oil;
microanalysis, found: C, 71.4; H, 7.5X; C14H1803 requires: C, 71-8; H, 7.74X; N~R (CDC13): 1.21 (3H, t), 2.58 (2H, m), 2.86 (2H, t), 3.37 (2H, d), 4.12 (2H, q), 5.02 (lH, s), 5.07-5.20 (2H, m), 5.90-6.10 (lH, m), 6.67-6.74 (lH, m), 6.90-6.98 (2H, m); m/z 234 (n).
Trifluoromethyl sulphonic anhydride (0.93 ml) was added dropwise over 5 minutes to a stirred solution of ethyl 3-1(3-allyl 4-hydroxy)phenyl]propionate (1.17 g) in pyridine (5 ml) at 0C under an atmosphere of argon. The mixture was stirred at 0C for 16 hours and then added to ice (50 g). The aqueous mixture was extracted with 2160~

ether (3x30 ml). The ether extracts ~ere combined, ~ashed ~ith ~ater (lx25 ml), lH aqueous hydrochloric acid (3x25 ml) and saturated brine (2x25 ml). The organic phase vas dried (~gS04) and evaporated to give ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (1.72 g) as an oil; NHR (CDC13): 1.22 (3H, t), 2.61 (2H, t), 2.95 (2H, t), 3.45 (2H, d), 4.12 (2H, q), 5.06-5.20 (2H, m), 5.83-5.90 (lH, m) and 7.05-7.20 (3H, m); m/z 367 (H+H).
The 3-ethynyl-3-hydroxyquinuclidine used as starting material vas obtained as follovs:-A solution of n-butyl lithium (100 ml of a 2H solution in pentane) ~as added portion-vise over a period of 20 minutes to a stirred solution of ethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at -70C. The mixture ~as stlrred for 1 hour at -70C. A solution of 3-quinuclidinone (2.4 g) in dry tetrahydrofuran (100 ml) ~as then added to the mixture and the mixture stirred for 1 hour at -70C. Hethanol (1 ml) vas then added to the d xture and the mixture allowed to warm to room temperature. The solvents ~ere removed by evaporation. nethanol (500 ml) and potassium carbonate (40 g) ~ere added to the residue and the mixture was stirred for 1 hour. The solvent ~as removed by evaporation. The residue vas triturated Yith water (500 ml) and then drled in vacuo to give 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193-197C; NHR
(DHS0-d6): 1.5-1.3(1H, m), 1.4-1.6(1H, m), 1.7-1.95(3H, m), 2.55-2.8(5H, m), 2.95(1H, d), 3.3(1H, d) and 5.4(1H, s); m~z 152 (n+H) .

E~nPLP 2 Using the method described in Example 1, but ~ith ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)acetate in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there ~as thus obtained 3-12-(2-allyl-4-ethosycarbonylmethylphenyl)-ethynyllq~in~clidin-3-ol as a solid, mp 84-6C; microanalysis, found:
C, 72.8; H, 7.60; N, 3.40X; C22H27N03 0.5 H20 requires C, 72.9; H, 7.60; N, 3.80%; NHR (CDC13) 1.25 (3H, t), 1.38-1.55 (lH, m), 1.60-1.78 (lH, m), 1.90-2.18 (3H, m), 2.20-2.50 (lH, m), 2.73-3.00 (4H, m), 3.08 (lH, d), 3.35 (lH, d), 3.51 (2H, d), 3.58 (2H, s), 4.14 (2H, q), W O 94/25459 21~ ~ 7 9 ~5 PCT/GB94/00910 5.0-5.10 (2H, m), 5.85-6.05 (lH, m), 7.07 (2H, m) and 7.35 (lH, d);
m/z 354 (~+H).
The ethyl 3-(3-allyl 4-trifluromethylsulphonyloxy-phenyl)acetate used as starting material was prepared from ethyl (2-allyl-4-hydroxyphenyl)acetate using the method described in Example 1 for the preparation of ethyl-3-l(3-allyl-4-hydroxy)phenyll-propionate. There vas thus obtained ethyl-3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)acetate as an oil;
NXR (CDC13): 1.25 (3H, t), 3.45 (2H, d), 3.61 (2H, s), 4.15 (2H, q), 5.08-5.18 (2H, m), 5.82-5.97 (lH, m) and 7.25 (3H, m); m/z 353 (~+H).
The ethyl (3-allyl-4-hydroxyphenyl)acetate vas obtained using the method in Rec. Trav. Pays Bas, 1952, 71, 879).

e-AnPL~ 3 Uslng the method described in Example 1, but vith ethyl (3-allyl-4-trifluoromethylsulphonyloxyphenyl)oxyacetate in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there vas thus obtained 3-[2-(2-allyl-4-etho~gcarbonyl ethylosyphenyl)-tLh~l]q~inucli~ir 3-ol as a solid, mp 98-99C; microanalysis, found:
C, 69.9; H, 7.30; N, 3.80Z; C22H27N04 0.5 H20 requires C, 70.0; H, 7.40; N, 3.70Z; NnR (CDC13): 1.30 (3H, t), 1.35-1.52 (lH, m), 1.60-1.75 (lH, m), 1.92-2.15 (3H, m), 2.15-2.45 (lH, m), 2.70-2.95 (4H, m), 3.07 (lH, d), 3.32 (lH, d of d), 3.51 (2H, d), 4.26 (2H, q), 4.60 (2H, s), 5.0-5.12 (2H, m), 5.86-6.02 (lH, m), 6.65-6.75 (2H, m) and 7.35 (lH, d); m/z 370 (n+H).
The ethyl (3-allyl-4-trifluoromethylsulphonyloxyphenyl)-oxyacetate used as starting material, was prepared as follovs.
Allyl bromide (3.37 B) was added to a stlrred suspension of ethyl 4-hydroxyphenoxyacetate (5.14 g) lprepared by method of hoser, J.A.C.S., (1950), 72, 1413) and potassium carbonate (3.90 g) in butan-2-one (50 ml). The reactlon mixture was heated at reflux for 12 hours. The reaction mixture was cooled to ambient temperature and then filtered. The filtrate was evaporated to give an oil which was purified by column chromatography on silica gel (nerck. Art. No. 7734) using a 4:1 (v/v) mixture of hexane and ethylacetate as eluent to give ethyl 4-allyloxyphenoxyacetate (6.41 g) as a colourless oil;

W O 94/254~ 7 9 S PCT/GB94/00910 microanalysis, found: C, 65.8; H, 7.20Z; C13H1604 requires C, 66-1; H, 6.83Z; NHR (CDCl3): 1.28 (3H, t), 4.25 (2H, q), 4.48 (2H, m), 4.57 (2H, s), 5.22-5.44 (2H, m), 5.92-6.12 (lH, m) and 6.84 (4H, s).
A solutlon of ethyl 4-allyloxyphenoxyacetate (2.0 g) in diphenylether (15 ml) was heated at reflux for 12 minutes. The reaction mixture was alloved to cool to ambient temperature and the reaction mixture vas poured onto a silica gel pad (nerck Art. No.
9385). Elution vith hexane followed by a 4:1 (vtv) mixture of hexane and ethyl acetate gave ethyl 3-allyl-4-hydroxyphenoxyacetate (1.62 g) as a solid, mp 52.8C; microanalysis, found: C, 66.3; H, 7.20X;
C13H1604 requires: C, 66:1; H, 6.83Z; NnR (CDC13): 1.28 (3H, t), 3.35 (2H, d), 4.25 (2H, q), 4.55 (2H, s), 4.73 (lH, s), 5.07-5.20 (2H, m), 5.88-6.10 (lH, m) and 6.62-6.78 (3H, m); m/z 237 (H+H).
The method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate was used to convert ethyl 3-allyl-4-hydroxyphenoxyacetate to ethyl (3-allyl-4-trifluoromethylsulphonyloxyphenyl)oxyacetate as a colourless oil, NHR (CDC13) 1.27 (3H, t), 3.42 (2H, d), 4.25 (2H, q), 4.60 (2H, s), 5.07-5.20 (2H, m), 5.80-5.97 (lH, m), 6.72-6.85 (2H, m) and 7.15 (lH, d); m/z 368 (n) .

E~AnPL~ 4 A mixture of ethyl 2-allyl-4-bromophenoxyacetate (912 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis (triphenylphosphine)-palladium (II) chloride (106 mg), copper (I) iodide (53 mg), triethylamine (3 ml) and dimethylformamide (6 ml) was stirred at 80C under an atmosphere of argon for 8 hours. The reaction mixture was cooled to ambient temperature and ~ater (100 ml) was added. The mixture was extracted with ethyl acetate (3x50 ml).
The ethyl acetate extracts were combined and filtered. The filtrate was washed with saturated brine solution (3x50 ml), dried (ngS04) and evaporated. The residue was purified by column chromatography on - Alumina (Fluka 507C) using ethyl acetate containing 2.5X methanol aseluent tO give 3-[2-(3-allyl-4-etho~ycarbonylmethylo~he..~l)-ethynyllquin~~rlidin-3-ol (220 mg) as a solid, mp 95.9C;
microanalysis, found: C, 70.7; H, 7.30; N, 3.50X; C22H27N04Ø25 H20 W O 94/25459 2 1 ~ 0 7 9 ~ PCT/GB94/00910 requires: C, 70.6; H, 7.35; H, 3.72Z; NHR (CDCl3): 1.28 (3H, t), 1.34-1.47 (lH, m), 1.52-1.72 (lH, m), 1.90-2.25 (3H, m), 2.25-2.60 (lH, m), 2.62-2.92 (4H, m), 2.97-3.09 (lH, d), 3.25-3.35 (lH, d of d), 3.42 (2H, d), 4.26 (2H, q), 4.62 (2H, s), 5.02-5.15 (2H, m), 5.88-6.08 (lH, m), 6.60-6.68 (lH, m) and 7.17-7.27 (2H, m); m/z 370 (H+H).
The ethyl 2-allyl-4-bromophenoxyacetate vas prepared as follovs.
Ethyl bromoacetate (1.68 g) vas added to a stlrred suspension of 2-allyl-4-bromophenol (2.13 g) and potassiun carbonate (1.50 g) in butan-2-one (15 ml). The mixture vas heated at reflux for 16 hours. The reaction mixture vas cooled to amblent temperature and filtered. Uater (100 ml) vas added to the filtrate and the aqueous phase vas extracted vith ethyl acetate (3x50 ml). The ethyl acetate extracts vere combined, vashed ~ith brine (2x25 ml), dried (ngS04) and evaporated to give a solid ~hich crystallised from hexane to give ethyl 2-allyl-4-bromophenoxyacetate (2.10 g), mp 70.5C;
microanalysis, found: C, 52.0; H, 5.10X; C13H15BrO3 requires: C, 52.2;
H, 5.05X; N~R (CDC13) 1.29 (3H, t), 3.42 (2H, d), 4.25 (2H, q), 4.58 (2H, s), 5.07-5.17 (2H, m), 5.88-6.18 (lH, m), 6.60 (lH, d) and 7.20-7.27 (2H, m); m/z 300 (H+H).
The 2-allyl-4-bromophenol vas prepared by the method of Claisen and Eisleb, Ann~len, 401, 1913, 38.

l~ll}!L~ S
Using the method described in Example 4, but Yith ethyl 4-bromophenoxyacetate in place of ethyl 2-allyl-4-bromophenoxy-acetate, there vas thus obtained 3-12-(4-ethoxycarbonylmethyl-ox~h~l)ethgnyllq~in~ in-3-ol as a solid, mp 137.1C;
microanalysis, found: C, 69.6; H, 7.40; N, 4.lX; C1gH23N04 requires:
C, 69.3; H, 7.04; N, 4.25Z; N~R (CDCl3): 1.27 (3H, t), 1.33-1.52 (lH, m), 1.54-1.77 (lH, m), 1.90-2.18 (3H, m), 2.20-2.70 (lH, m), 2.72-2.97 (4H, ~), 3.03 (lH, d), 3.31 (lH, d of d), 4.21 (2H, q), 4.60 (2H, s), 6.78-6.88 (2H, d) and 7.30-7.40 (2H, d); m/z 330 (H+H).
The starting ethyl 4-bromophenoxyacetate was prepared by the method of Adams and Po~ell, J.A.C.S. 42, 1920, 656.

21607~

PLe 6 Using the method described in Example 4, but vith ethyl 4-bromophenyl acetate in place of ethyl-2-allyl-4-bromophenoxy-acetate, there vas thus obtained 3-12-(4-etho~ycarbonyl ethylphenyl)-ethyngllq~in~rl~i -3-ol as a solid, mp 132.5C; microanalysis: C, 72.6; H, 7.60; N, 4.30Z; C1gH23N03 requires: C 72.8; H 7.40; N, 4.47Z;
N~R (ICD312SO): 1.18 (3H, t), 1.30 (lH, m), 1.59 (lH, m), 1.75-2.00 (3H, m), 2.67 (4H, t), 2.81 (lH, d), 3.07 (lH, d), 3.68 (2H, s), 4.08 (2H, q), 5.55 (lH, s) and 7.20-7.40 (4H, q); m/z 314 (H+H).

Le 7 A mixture of 4-(2-methoxyethoxy)-iodobenzene (13.9 g), 3-ethynyl-3-hydroxyquinuclidine (7.55 g), bis(triphenylphosphine)--p~ dium (II) chloride (1.75 g), copper (I) iodide (875 mg), triethylamine (25 ml) and dimethylformamide (50 ml) ~as stirred under an atmosphere of argon Yhen an initial exothermic reaction ensued, the reactlon temperature rislng to 50C. The reactlon mixture vas then stlrred at amblent temperature for a further 16 hours. The trlethylamine and dimethylformamlde vere removed by evaporatlon. The resldue ~as dlssolved ln dichloromethane (500 ml) and vashed ~ith a 2H
aqueous sodium hydroxide solution (2x50 ml), ~ater (50 ml), dried (HgS04) and evaporated. The residue ~as purified by flash column chromatography on silica gel (Herck Art. No. 9385) uslng a gradlent of 5Z methanol ln dlchloromethane contalning lZ 0.880 ammonia to 10Z
methanol in dichloromethane containing 1% 0.880 ammonia as eluent to give a solld (15 g). Thls solld vas further purlfled by crystalllsatlon from acetonitrile to give 3-[2-{4-(2~ Lho-~_Lho~
phenyl~eLL~ ql~m~rlldin-3-ol (7.2 g) as a solid mp 148-149C;
microanalysis; found C 71.9; H 7.9; N 4.6X; C18H23N03 requires: C
71.7; H 7.69; N 4.65%; NHR (lCD3]2S0): 1.2-1.35 (lH, m), 1.5-1.65 (lH, m), 1.78-1.97 (3H, m), 2.6-2.73 (4H, m), 2.75-2.85 (lH, d), 2.99-3.09 (lH, d), 3.3 (3H, s), 3.6-3.68 (2H, m), 4.05-4.13 (2H, m), 5.46 (lH, br), 6.88-6.95 (2H, d) and 7.28-7.35 (2H, d); m/z 302 (H+H).
The 4-(2-methoxyethoxy)iodobenzene used as starting material ~as obtained as follo~s.

~lfi~ ~9~
W O 94/2~459 PCT/GB94/00910 A mixture of 4-iodophenol (20 g), 2-bromoethylmethyl ether (11.4 g), potassiu~ carbonate (12.5 g) and dimethylformaoide (100 ml) vas stirred at 80C for 4 hours. A further portion of 2-bromoethylmethyl ether (2.24 g) and potassium carbonate (2.5 g) vas then added and the mixture stirred at 80C for a further 1 hour. The dioethylforoamide vas removed by evaporationO The residue vas treated vith a 2H aqueous sodium hydroxide solution (S0 ml) and the mixture extracted vith diethyl ether (3x50 ml). The ethereal extracts vere coobined, vashed vith 2H aqueous sodium hydroxide solution (2x20 ml), brine (20 ml), dried (HgS04) and evaporated to give 4-(2-~ethoxyethoxy)iodobenzene (23 g) as a vhite solid, m.p. 36-37C.
NHR (ICD312S0): 3.3 (3H, s), 3.6-3.7 (2H, m), 4.0-4.1 (2H, m), 6.72-6.82 (2H, d) and 7.52-7.62 (2H, d).

E~PLE 8 A lH solution of lithium aluminium hydride in tetrahydrofuran (10 ml) vas added over a period of 20 minutes to a stirred solution of 3-[2-{4-(2-methoxyethoxy)phenyl~ethynyl3quinuclidin-3-ol (3.01 g) in dry tetrahydrofuran (100 ml) under an atmosphere of argon at 40C.
The reaction mixture vas then stirred at a~bient temperature for 16 hours. ~ater (0.4 ml) and 2H aqueous sodium hydroxide solution (0.8 ml) vas then added to the reaction mixture dropvise folloved by a further quantlty of vater (1.2 ml). The resulting precipitate vas collected by filtration and the filtrate vas evaporated. The residue from the filtrate vas crystallised from acetonitrile to give 3-l(E)-2-{4-(2 ~LhG~Lhv.~)phenyl}~inyllql~in~lel~n-3-ol (2.54 g) as a solid, mp 164-166C, microanalysis, found C,71.4; H,8.6; N,4.SZ;
C18H25N03 requires: C,71.3; H,8.31; N,4.62Z; N~R ([CD3l2S0): 1.15-1.32 (lH, m), 1.38-1.52 (lH, m), 1.62-1.74 (2H, m), 1.95-2.1 (lH, m), 2.58-2.6 (SH, m), 2.82-2.92 (lH, d), 3.3 (3H, s), 3.6-3.67 (2H, m), 4.03-4.1 (2H, m), 4.66 (lH, s), 6.38-6.45 (lH, d, J = 16.67), 6.51-6.58 (lH, d, J = 16.67), 6.86-7.12 (2H, d) and 7.32-7.38 (2H, d);
m/z 304 (H+H).

2~ 607~

~PL~ 9 A mixture of 3-12-{4-(2-methoxyethoxy)phenyl)ethynyll-quinuclidin-3-ol (1.8 g) in ethanol (200 ml) and a catalyst of lOZ
(w/v) palladlum on carbon (100 mg) was stirred under an atmosphere of hydrogen until hydrogen uptake ceased. The palladium/carbon catalyst vas removed by filtration and the filtrate was evaporated. The resldue was crystalllsed from a 3:1 (v/v) mlxture of cycloheYane ethylacetate to glve 3-12-l4-(2--aLho-~Lho~)phenyl)ethyllq~ olidin-3-ol (700 mg) as a solld, mpt 116-117C. Hlcroanalysls, found C,71.1; H,9.2; N,4.5Z;
C18H27N03 requlres: C,70.8; H,8.9; N,4.59Z; NnR (lCD312SO): 1.15-1.35 (lH, m), 1.4-1.6 (lH, m), 1.65-1.78 (2H, m), 1.9-2.08 (lH, m), 2.45-2.8 (lOH, m), 3.3 (3H, s), 3.6-3.68 (2H, m), 4.0-4.08 (2H, m), 4.3 (lH, br), 6.78-6.86 (2H, d), 7.05-7.13 (2H, d); m/z 306 (~+H).

~PL~ 10 Bls(trlphenylphosphine)-pall~dium (II) chloride (95mg) ~as added to a stirred mixture of 3-ethynyl-3-hydroxyquinuclidine (400~g), 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (704mg) and copper (I) lodlde (48mg) in dimethylformamlde (D~F) (5.5ml) and trlethylamine (2.7ml) at amblent temperature and under an atmosphere of argon. The mlxture ~as heated at 65C for 14 hours, cooled to a~blent temperature, diluted vith 2n aqueous sodium hydroxide (20ml) and extracted ~ith diethyl ether (5 x lOOml). The ethereal extracts vere combined, washed ~ith ~ater (lOOml) and saturated brine (lOOml), dried (~2C03) and evaporated. The residue vas crystallised from acetonitrile to glve 3-12-(4-{2--cLLo,~tho,~)-3,5-dimethylphenyl)-ethynyl]q~in~r~ -3-ol (130mg) as a solid, m.p. 120C;
microanaylsis, found: C, 72.4; H, 8.2; N, 4.1Z; C20H27N03 requires: C, 72.9; H, 8.3; N, 4.2Z; NnR(ICD3)2SO): 1.3(1H,m), 1.57(1H,m), 1.9(3H,m), 2.21(6H,s), 2.65(4H,m), 2.8(1H,d), 3.02(1H,d), 3.31(3H,s), 3.61(2H,m), 3.87(2H,m), 5.5(1H,br) and 7.07(2H,s); m/z 330 (n+H).
The 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane used as starting material was obtained as follows.
Lithium hydride (200mg) was added to a stirred solution of 4-bromo-2,6-dimethylphenol (65g) in DHF at ambient temperature. Uhen VVO 94/25459 216 ~ 7 ~ ~ PCT/GB94/00910 evolution of hydrogen had ceased, ethylene carbonate (31.9g) Yas added and the mixture vas heated at 150C for 12 hours. The DHF vas removed by evaporation and the cooled residue vas dissolved in ethyl acetate (500ml). The ethyl acetate solution vas vashed vith vater (2 x lOOml) and then vith saturated brine (lOOml), dried (ngS04) and evaporated.
The residue vas crystallised from methanol to give 2-(4-bromo-2,6-dlmethylphenoxy)ethanol (Slg), m.p. 47-48C.
NXR (CDC13): 2.21(6H,s), 3.86(2H,m), 3.93(2H,m), 7.12(2H,s).
A solution of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (lSg) in methylene chloride (1OOml) vas added to a stirred solution of sodium hydroxide (SOg) in vater (50ml) at 5C. Dimethyl sulphate (8.6ml) vas added dropvise to the stirred solution at 5C over 30 minutes. The mixture vas stirred at ambient temperature for 12 hours.
Di~ethylsulphate (Sml) vas added at ambient temperature and the mixture stirred for a further 2 hours. The mixture vas cooled to 0C
and a solution of ammonia (lOml, density - 0.88g/cm3) vas added. The mixture vas stlrred for 20 minutes, diluted Yith iced Yater (500~1).
The methylene chloride phase vas removed and the aqueous pha~e extracted vith methylene chloride (2 x 150ml). The organic extracts Yere combined, Yashed vith vater (2 x lOOml), saturated brlne (lOOml) and evaporated. The residue Yas distilled using a short path distillation apparatus (furnace temperature 120C/0.08 bar) to give 1-(4-bromo-2~6-dimethylphenoxy)-2-methoxyethane (11.6g); NXR(CDC13):
2.34(6H,s), 3.52(3H,s), 3.78(2H,m), 3.96(2H,m) and 7.2(2H,s).

~PL~ 11 Using the procedure described in Example 10, but using 1-(4-bromobenzyloxy)-2-methoxyethane in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there vas thus obtained 3-[2-(4-{2--ethG~Lho~yxethyl}phenyl)ethynyll_ qll~n~ idin-3-ol (14Z) as a solid, m.p. 127-128C; microanalysis, found: C, 71.9; H, 7.8; N, 4.4X; ClgH25N03 requires: C, 72.4; H, 8.0;
N, 4.4Z; NHR (lCD312SO): 1.30(1H,m), 1.61(1H,m), 1.95(3H,m), 2.69(4H,t), 2.83(1H,d), 3.07(1H,d), 3.25(3H,s), 3.49(2H,m), 3.56(2H,m), 4.50(2H,s), 5.58(1H,br), 7.30(2H,d) and 7.39(2H,d); m/z 316 (H+H).

wo 94/254ggl ~ 0 7 ~ 5 The 1-(4-bromobenzyloxy)-2-methoxyethane used as starting material vas obtained as follovs.
2-nethoxyethanol (5.0g) ~as added to a stirred suspension of sodium hydride (2.64g of a 60X mineral oil suspension) in DHY (200ml) at ambient temperature and under an atmosphere of argon. The stirred mixture vas heated to 60C and then cooled to 5C. Solid 4-bromobenzyl bromide (15g) vas added in one portion. The mixture vas stirred for 12 hours at ambient temperature, then for 1 hour at 60C
and cooled. The mixture vas diluted ~ith iced vater (600ml) and extracted ~ith ethyl acetate (3 x 200ml). The ethyl acetate extracts ~ere combined, vashed vith 2~ aqueous hydrochloric acid (lOOml), vater (2 x lOOml), saturated brine (1OOml), dried (hgS04) and evaporated.
The residue, an oil, vas distilled using a short path distillation apparatus (furnace temperature 125C/0.05 bar) to give 1-(4-bromobenzyloxy)-2-methoxyethane (9.8g); NHR (CDC13): 3.39(3H,s), 3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d).

ESA~YL~ 12 Using a similar procedure to that described in Example 10, but using 1-(4-bromophenoxy)-2-methoxy-1-methoxymethylethane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)--2-methoxyethane, there vas obtained 3-l2-(4-~2--~Lh~ kLhG~-methyletho.~}pbenyl)~Lh~ q~ rl~ 3-ol (33Z yield) as a solid, m.p. 125 - 127C (after recrystallisation from acetonitrile);
microanalysis, found C, 69.6; H, 8.0, N, 4.0Z; C20H27N04 requires: C, 69.S; H, 7.9; N, 4.1X; NHR(ICD3]2SO): 1.2-1.4(1H,m), 1.5-1.65(1H,m), 1.7-2.0(3H,m), 2.6-2.75(4H,t), 2.75-2.9(1H,d), 3.0-3.1(1H,d), 3.25(6H,s), 3.5-3.6(4H,d), 4.55-4.7(1H,m), 5.5(1H,s), 6.9-7.0(2H,d) and 7.25-7.35(2H,d); mtz 346(h+H).
The 1-(4-bromophenoxy)-2-methoxy-1-methoxymethylethane used as a starting material was obtained using a similar procedure to that described for the preparation of the starting material in Example 14, but starting from 4-bromophenol and 1,3-dimethoxypropan-2-ol (obtained as described in JACS 1939, 61, 433). There ~as thus obtained 1-(4-bromophenoxy)-2-methoxy-1-methoxymethylethane; NnR(CDC13):
3.4(6H,s), 3.6(4H,s), 4.4-4.5(1H,m), 6.8-6.9(2H,d) and 7.3-7.4(2H,d).

W O 94/25459 21~ O ~ 3 ~ PCT/GB94/00910 E~AnrLe 13 Using a similar procedure to that described in example 10, but using 1-(4-bromo-2,6-dimethylphenoxy)-2-ethoxyethane as startlng material in place of l-(4-bromo-2~6-dimethylphenoxy)-2-methoxyethane~
there vas obtained 3-[2-(4-{2-eLhG~Lho~y)-3,5-di ethylphenyl)-ethynyllq~ i 3-ol (36X yield) as a solid, m.p. 113-115C (after recrystallisation from acetonitrile); microanalysis, found C, 73.1; H, 8.6, N, 4.4X; C21H29N03 requires: C,73.4; H, 8.5; N, 4.1Z NnR(CDCl3) 1.2-1.3(3H,t), 1.3-1.5(1H,m), 1.5-1.7(1H,m), 1.9-2.2(3H,m), 2.25(6H,s), 2.75-2.95(4H,t), 2.95-3.05(1H,d), 3.2-3.4(1H,d of d), 3.5-3.7(2H,q), 3.7-3.8(2H,q), 3.9-4.0(2H,q) and 7.1(2H,s); m/z 344(H+H)-The 1-(4-bromo-2,6-dimethylphenoxy)-2-ethoxyethane used as starting material vas obtained in an analogous manner to that for the preparation of 1-(4-bromo-2,6-dimethylphenoxy-2-methoxy ethane in Example 10 but using diethylsulphate as the alkylating reagent. There Yas thus obtained 1-(4-bromo-2,6-dimethylphenoxy)-2-ethoxyethane, NMR(CDCl3): 1.2-1.3(3H,t), 2.25(6H,s), 3.55-3.65(2H,q), 3.7-3.8(2H,d of d), 3.85-3.95(2H,d of d) and 7.15(2H,s).

~SAnrL~ 14 Using a similar procedure to that described in Example lO, but using 1-(4-bromo-2,6-dimethylphenoxy)-2-phenoxyethanol as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane and extracting the aqueous mixture obtained after diluting the reaction mixture Yith 2~ aqueous sodium hydroxide Yith dichloromethane instead of diethyl ether, there Yas obtained 3- l 2- ( 4- {2-p~v~ o~} -3 ~ s-diJethyl p~ ,~,l)eth~lyll ql~in~c l i di ne-3-ol(28Z yield) as a solid, m.p. 141-142C (after recrystallisation from acetonitrile); microanalysis, found: C, 76.2; H, 7.4; N, 3.5Z;
C25H29N03 requires: C, 76.7, H, 7.5; N, 3.6X; in 28X yield N~R
([CD3]2S0): 1.2-1.4(1H,m), 1.5-1.65(1H,m), 1.7-2.0(3H,m), 2.15-2.3(6H,s), 2.6-2.75(4H,t), 2.75-2.9(1H,d), 2.95-3.1(1H,d), 4.0-4.3(4H,m), 5.5(1H,s), 6.9-7.05(3H,m), 7.1(2H,s) and 7.25-7.4(2H,m); m/z 392 (~+H).

`~160~55 The 1-(4-bromo-2,6-dimethylphenoxy)-2-phenoxyethane used as a starting material ~as obtained as follo~s.
A solution of diethyl azodicarboxylate (3.5g) ln tetrahydrofuran (5ml) vas added portionYise over a period of 30 minutes to a stirred solution of triphenylphosphine (5.2g), phenol (1.88g) and 2-(4-bromo-2,6-dimethylphenoxy)ethanol in dry tetrahydrofuran (30ml) under an atmosphere of argon at 0C. The resultant mixture ~as alloved to attain ambient temperature and stirred for a further 18 hours. The tetrahydrofuran vas renoved by evaporation and the residue vas purified by flash column chromatography on silica gel (herck Art No. 9385) using 5X ethyl acetate/hexane as eluent to give l-(4-bromo-2,6-dimethylphenoxy)2-phenoxyethane (1.07g) as a solid, m.p. 49 -50C (after recrystallisation from hexane).

~PL~ 15 Using a similar procedure to that described in Example 10, but using 1-(4-bromophenoxy)-2-phenoxyethane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane and extracting the aqueous mixture obtained after diluting the reaction mixture vith 2n aqueous sodlum hydroxide vith dichloromethane instead of diethyl ether, there vas obtained 3-12-(4-~2-phen~ hG~}phengl)ethgngllq~ clid~n-3-ol (18Z yield) as a solid, m.p. 207-208C (after recrystallisation from acetonitrile); microanalysis, found: C,74.7; H, 6.9; N, 3.8Z
C23H24N03. 0.3H20 requires: C, 74.9; H, 7.0; N, 3.8X; N~R (ICD3]2SO):
1.2-1.4(1H,m), 1.5-1.65(1H,m), 1.7-2.0(3H,m), 2.55-2.75(4H,t), 2.75-2.9(1H,d), 3.0-3.15(1H,d), 4.2-4.4(4H,m), 5.5(1H,s), 6.9-7.05(5H,m) and 7.2-7.4(4H,m); m/z 364 (H+H).
The 1-(4-bromophenoxy)-2-phenoxyethane (m.p. 101-102C) used as a starting material ~as obtained in a similar manner to that for the preparation of 1-(4-bromo-2,6-dimethylphenoxy)-2-phenoxyethane described in Example 15, but using 2-(4-bromophenoxy)ethanol and phenol as starting materials.

W 0 94/25459 216 Q 7 9 ~ PCT/GB94/00910 e~A~PL~ 16 Using a similar procedure to that described in Example 10, but using 1-(4-bromo-3,5-dimethylphenoxy)-2-methoxyethane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there was obtained 3-12~ 2- etho~Lhosy)-2,6-di ethylphenyl)-ethynyllq~in~ n-3-ol (7X yield) as a solid, m.p. 140-142C (after recrystallisation from acetonitrile); microanalysis, found: C, 72.8;
H, 8.1, N, 4.4X; C20H27N03 requires: C, 72.9; H, 8.3; N, 4.3X; NHR
(ICD3l2SO): 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.3(6H,s), 2.6-2.8(4H,m), 2.8-3.0(1H,d), 3.05-3.2(1H,d), 3.25(3H,s), 3.6-3.7(1H,d of d), 4.0-4.1(1H,d of d) 5.5(1H,s) and 6.65(2H,s); m/z 330 (n+H).
The 1-(4-bromo-3,5-dimethylphenoxy)-2-methoxyethane used as startin~ material was obtained in an analogous manner to that for the preparation of 3-(4-bromo-2,6-dimethylphenoxy)tetrahydrofuran described in Example 14, but using 4-bromo-3,5-dimethylphenol and 2-methoxyethanol as starting materials. There was thus obtained 1-(4-bromo-3,5-dimethylphenoxy)-2-methoxyethane; NHR(CDC13):
2.4(6H,s), 3.4(3H,s), 3.65-3.75(2H,m), 4.0-4.1(2H,m) and 6.65(2H,s) E~AnYLe 17 A mixture of 3-ethynyl-3-hydroxyquinuclidine (574mg), methoxyethyl 2-methoxyethoxy-5-iodobenzoate (1.6g), bis(triphenylphosphine)palladium (II) chloride (135mg), copper (I), iodide (75mg), trlethylamine (5ml) and dimethylformamide (lOml) ~as stirred at 70C under an atmosphere of argon for 2 hours. The triethylamine and dimethylformamide were removed by evaporation. The residue vas purified by flash column chromatography on slllca gel (nerck Art No 9385) using a mixture of 3X triethylamine in ethyl acetate as eluent to give, after trituration with dichloromethanetpentane (1:1, lOml), 3-l2-(4-(2--etho~LhG~)-3-(2- ethosyethosycarbonyl)phenyl)ethynyllqllin~lo~ n-3-ol (350mg) as a colourless solid, m.p. 100-102C; microanalysis, found: C, 65.7; H, 7-4; N, 3-4X; C22H29N06 requires: C,65.5; H, 7.2; N, 3.5Z; NnR
(lCD312SO): 7.6(1H,d), 7.5(1H, d of d), 7.2(1H,d), 5.5(1H,s), 2~ 607~, 4.3(2H,m), 4.2(2H,m), 3.7-3.6(4H,m), 3.32(3H,s), 3.30(3H,s), 2.9(2H,m), 2.7(4H,m), 2-1.8(3H,m), 1.6(1H,m), 1.3(1H,m); m/z 404 (H+H).
The methoxyethyl 2-methoxyethoxy-5-iodobenzoate used as starting material vas obtained as follovs.
A mixture of 2-hydroxy-5-lodobenzoic acld (1.32g), bromoethyl methyl ether (1.39g), potassium carbonate (1.5g) and dimethylformamide (10ml) vas stirred at 70C under an atmosphere of argon for 14 hours. The mixture vas cooled to ambient temperature, diluted vith vater (lOOml) and extracted vith ethyl acetate (lOOml).
The organic extract vas vashed with aqueous sodium carbonate solution, dilute aqueous hydrochloric acid, vater and saturated brine and dried ~HgS04). E~aporation gave methoxyethyl 2-methoxyethoxy-5-iodobenzoate (1.64g) as a yellov oil; N~R (ICD3)2SO): 7.7(2H,m), 6.9(1H,d), 4.2(2H,m), 4.0(2H,m), 3.5(4H,m), 3.20(3H,s) and 3.19(3H,s); m/z 3so(n) .

A mixture of 3-ethynyl-3-hydroxyquinuclidine (453mg), methoxyethyl 4-bromo-2-chlorophenyl ether (0.97g), bis(triphenylphosphine)p21ladlum (II) chloride (105mg), copper (I) iodide (55mg), triethylamine (5ml) and dimethylformamide (lOml) vas stirred at 70C under an atmosphere of argon for 2 hours. The triethylamine and dimethylformamide vere removed by evaporation. The residue vas purified by flash column chromatography on silica gel (Herck Art. No. 9385) using a mixture of 10X methanol in dichloromethane containing 1Z ammonia (density, 0.880 g/cm3) as eluent. The residue vas crystallised from acetonitrile to give 3-~2-(3-chloro-4-(2--ethG,~LLG~)phenyl)~Lh~ q in~cli~in-3-ol (0.52g) as a colourless solid, m.p. 138-139~C; microanalysis, found:
C, 64.1; H, 6.7; N, 4.1%; C18H22ClN03 requires: C, 63.9; H, 6.6; N, 4.1X; NHR (lCD312SO): 7-5(1H,d), 7.3(1H,d of d), 7.1(1H,d), 5.5(1H,s), 4.2(2H,m), 3.7(2H,m), 3.3(3H,s), 2.8(2H,m), 2.7(4H,m), 2-1.8(3H,m), 1.6(1H,m) and 1.3(1H,m); m/z 336(H+H).
The methoxyethyl 4-bromo-2-chlorophenyl ether used as starting material was obtained as follows.

W 0 94/25459 ~ 7 9 ~
~ PCT/GB94/00910 A mixture of 4-bromo-2-chlorophenol (1.04g) bromoethyl methyl ether (0.70g), potassium carbonate (0.76g) and dimethylfor~amide (5ml) ~as stirred at 70C under an atmosphere of argon for 14 hours. The mixture was cooled to amblent temperature, d~luted ~ith Yater (lOOml) and extracted ~ith ethyl acetate (100 d ).
The organic extract ~as ~ashed ~ith aqueous sodium carbonate, saturated brine and dried (HgS04). Evaporation gave methoxyethyl 4-bromo-2-chlorophenyl ether (1.14g) as a colourless oil; N~R
(ICD3l2SO): 7.7(1H,d), 7.5(1H,dd), 6.9(1H,d), 4.2(2H,m), 3.7(2H,m) and 3.3(3H,s); m/z 264/266 (h+H).

~A~rL~ 19 A mixture of 2-benzyl-1-phenyltrifluoromethane s~lphon~te (1.27g), 3-ethynyl-3-hydroxyquinuclidine (604mg), bis(triphenylphosphlne)-palladium (II) chloride (140mg), copper (I) iodide (70mg), triethylamine (4ml) and dimethylformamide (8ml) was stirred at 70C under an atmosphere of argon for 3 hours. The triethylamine and dimethylfor~amide ~ere removed by evaporation. A 2h aqueous solution of sodium hydroxide (25ml) vas added to the residue and the mixture extracted vith dichloromethane. The organic extracts vere combined, vashed Yith vater and saturated brine, dried (hgS04) and evaporated. The residue vas purified by flash column chromatography on silica gel (nerck Art 9385) using 10X methanol in dichloromethane cont~ining 1X ammonia (denslty, 0.880g/cm3) as eluent to give (after re-crystallisation from acetonitrile) 3-~2-(2-benzylphenyl)ethynyllq~ c~ n-3-ol (175mg) as a solid, m.p.
156-157C; microanalysis, found: C, 82.5; H, 7.5; N, 4.5X; C22H23NO.
0.1CH3CN requires: C, 82.9; H, 7.3; N, 4.79Z; NhR(ICD3]2SO):
1.20-1.35(1H,m), 1.40-1.56(1H,m), 1.65-1.80(1H,m), 1.80-1.95(2H,m), 2.05(CH3CN solvent), 2.50-2.70(4H,m), 2.75-2.85(1H,d), 2.94-3.04(1H,d), 4.10(2H,s), 5.57(1H,s), 7.12-7.33(8H,m) and 7.35-7.43(1H,d); m/z 318 (H+H).
The 2-benzyl-1-phenyltrifluoromethane sulphonate used as starting material ~as prepared as follo~s.
Trifluoromethane sulphonic anhydride (6.5ml) was added drop~ise tO a stirred solution of 2-hydroxydiphenylmethane (6.45g) in 21507~

pyridine (50ml) at 0C under an atmosphere of argon. The reaction mixture was stirred for 2.5 hours at 0C and then alloved to warm to +15C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, saturated brlne, dried (HgS04) and evaporated. The residue vas purified by flash column chromatography on silica gel (~erck Art 9385) uslng SX ethyl acetate/hexane as eluent to give 2-benzyl-1-phenyltrifluoromethane sulphonate as an oil (9.lg);
nicroanalysis, found: C, 53.1; H, 3.6X; C14H11F303S requires: C, 53-2;
H, 3-51Z; N~R(¦CD3]2S0): 4.05(2H,s) and 7.14-7.49(9H,m); m/z 316(~).

~AnPLe 20 A solution of sodium hydroxide (8.5g) in water (90ml) vas added at ambient temperature to a stirred mixture of quinuclidin-3-one (8.9g), 2-hydroxydiphenylmethane (13.0g) and trimethylsulphoxonium iodide (31.2g) in toluene (150ml). The mixture vas stirred at ambient temperature for 3 days under an atmosphere of argon.
The mixture was filtered through diatomaceous earth and the filtercake was vashed with ethyl acetate (3 x 60ml). The filtrate and vashings vere combined and the organic layer was separated and retained. The aqueous layer was extracted vith ethyl acetate (4 x 130ml). The retained organic layer and the ethyl acetate extracts were combined and extracted with 2~ aqueous hydrochloric acid (4 x 25ml). The acid extracts were combined, washed vith ethyl acetate (2 x lOOml), cooled in ice, basified vith 40X sodium hydroxide solution (30ml) and extracted with ethyl acetate (4 x 70ml). The ethyl acetate extracts were combined, washed with saturated brine (50ml), dried (Na2S04) and evaporated. The residue was purified by column chromatography on silica gel (~erck 7736) to give (after trituration with n-pentane) 3-(2-benzylphenoxymethyl)quinuclidin-3-ol (0.13g) as a colourless solid, m.p. 71-73C; microanalysis, found: C, 77.1; H, 7.8;
N, 4.5Z; C21H25N02 0.2H20 requires: C, 77.1; H, 7.8; N, 4.3Z;
NnR(CDCl3): 1.2-1.4(1H,m), 1.4-1.6(2H,m), 1.65-2.1(3H,m), 2.5-3.0(6H,m), 3.65-3.8(1H,d), 3.9-4.1(3H,m), 6.8-6.9(1H,d), 6.9-7.0(1H,m) and 7.05-7.35(7H,m); m/z 324(~+H).

W 0 94/25459 21 fi Q 7 ~ ' PCT/GB94/00910 e2A~PL~ 21 An ice-cooled solution of 3n aqueous hydrochloric acid (9ml) in acetone (27ml) vas added eo 3-(2-benzyl-4-propionamido-phenoxymethyl)-3-hydroxyquinuclidine borane complex (1.9g). The latter dissolved im~ediately and the resulting colourless solution vas stirred at 5C for 1.5 hours. The reaction mixture vas evaporated and the residue Yas dissolved in 2h aqueous hydrochloric acld (SOml).
This acidic aqueous solution ~as vashed vith ethyl acetate (3 x 25ml), basified vith solid sodium carbonate, and extracted with ethyl acetate (3 x 70ml). The ethyl acetate extracts were combined, dried (Na2S04), and evaporated. The residue was dissolved in hot ethyl acetate (lOml) and the resulting solution was added to a hot solution of fumarlc acid (0.46g) in ethyl acetate (40ml)/ethanol (lOml). The cooled mixture was evaporated to give a foam. Thls vas triturated vith ethyl acetate/ether to give a solid which vas stored under vacuum over phosphorus pentoxide for 18 hours. There vas thus obtained 3-(2-benzyl-~-propionarid~p~ ymethyl)q-l~n~ n-3-ol fumarate (1.2g) as a solid, m.p. 70-85C; microanalysis, found: C, 63.2; H, 7.1; N, 4.7Z; C24H30N203 fumarate, 1.0 H20, 0.33 ethyl acetate, 0.13 ether requires: C, 63.2; H, 7.1; N,4.9X; NHR (ICD3l2SO):
1.0-1.1(3H,t), 1.4-1.8(3H,m), 2.0-2.3(4H,m), 2.8-3.2(6H,m), 3.9-4.1(4H,m), 4.5-6.5(1H+H20), 6.45-6.55(2H,s), 6.85-7.0 (lH,d), 7.1-7.35(6H,m), 7.4-7.5(1H,m), 9.6-9.7(1H,s); m/z 395 (h+H).
The 3-(2-benzyl-4-propionamidophenoxymethyl)-3-hydroxy-quinuclidine borane complex used as starting material was obtained as follovs.
A solution of borane-tetrahydrofuran complex (135 ml of a lH
solution in tetrahydrofuran) vas added portionvise over a period of 30 minutes to a stirred solution of 3-quinuclidinone (16.9 g) in dry tetrahydrofuran (300 ml) at -70C. The mixture vas stirred at -70C
for 30 minutes. ~ater (20 ml) vas added to the reaction mixture at -70C. The solvent vas removed by evaporation. A saturated solution of brine (250 ml) was added to the residue and the mixture basified by addition of solid sodium carbonate. The mixture vas extracted with dichloromethane (4 x 100 ml). The dichloromethane extracts vere combined, silica gel (~erck 9385, 60 g) added and the mixture 2 ~ O "1 ~

evaporated to give a free floving povder. This pre-absorbed material on silica gel vas purified by flash column chromatography on a further portion of silica gel using a mixture of 25X ethyl acetate/pentane as eluent to give 3-qulnuclidinone borane complex (17.0 g) as a colourless solid, m.p. 162-164C; N~R (CDC13): 0.7-2.3(3H, br), 2.0-2.3(4H, m), 2.7(1H, m), 3.0-3.4(4H, m) and 3.5(2H, s).
Povdered trimethyl sulphoxonium iodide (24.4 g) vas added portionvise to a stirred, ice-cooled, suspension of sodiu~ hydride (60X v/v dispersion in mineral oil, 4.4g; the oil vas removed by vashing the solid vith petroleum ether) in dry dimethyl formamide (140 ml) under an atmosphere of argon vhilst maintaining the tenperature at 10 to 15C. The mixture vas alloved to varm to room teoperature.
Solid 3-q~inuclidinone borane complex (15.5 g) vas added to the stirred mixture vhilst maint~n~ng the temperature at 25-30C using an ice-bath. The mixture vas then stirred at room temperature for 16 hours.
The mixture was poured into vater (1400 ml) and the mixture vas extracted vith ethyl acetate (4 x 400 ml).
The ethyl acetate extracts vere combined, vashed vith vater (3 x 300 ml), dried (Na2S04) and evaporated. The residue vas purified by flash column chromatography on silica gel using dichloromethane as eluent to give 3-methylenequinuclidine oxide borane complex (13.8 g) as a colourless solid, m.p. 74-77C; microanalysis, found: C, 63.1; H, 10.6; N, 9.2X; C8H16BNO requires: C, 62.8; H, 10.5; N, 9.2X; NhR
(CDC13): 0.6-2.3(3H, br), 1.6(1H, m), 1.7-1.9(1H, m), 1.9-2.0(2H, m), 2.1-2.3(1H, m), 2.8(2H, q) and 2.9-3.4(6H, m); m/z 152 (h-H).
Solid potassium carbonate (1.6g) vas added to a solution of 2-benzyl-4-propionamidophenol (1.5g) and 3-methylene quinuclidine oxide borane complex (0.9g), in dry dimethylformamide (lOml) under an atmosphere of argon. The mixture was stirred for 3 hours at 70~C.
The mixture vas poured into vater (lOOml) and the mixture vas extracted with ethyl acetate (3 x 70ml). The ethyl acetate extracts vere combined, washed with 2~ aqueous sodium hydroxide solution (2 x 25ml) and water (2 x 25ml), dried (Na2S04) and evaporated to give a gum (2.6g). This gum was purified by flash column chromatography on silica gel (~erck Art No 9385) using 20% ethyl acetate/dichloromethane W 0 94/25459 216 0 ~ 9 ~ PCT/GB94/00910 as eluent. There was thus obtained 3-(2-benzyl-4-propionamido-phenoxymethyl)-3-hydroxyquinuclidine borane complex as a gun (2.0g);
N~R(CDC13): 0.5-2.5(3H, v.br), 1.2-1.3(3H,t), 1.4-1.75(3H,m), 1.9-2.25(3H,m), 2.3-2.5(2H,q), 2.7-3.2(6H,m), 3.7-3.9(2H,q), 3.9-4.0(2H,s), 6.7-6.8(1H,d), 7.05-7.5(8H,m); m/z 407 (H-H).
The 2-benzyl-4-propionamidophenol used as starting material vas prepared as follovs.
Sodiu~ nitrite (9.48g) vas added to a solution of sulphanilic acid (24.9g) and sodiu~ carbonate (6.78g) vhilst maintaining the temperature of the reaction mixture at 5C. The resulting mixture vas carefully poured into a mixture of concentrated hydrochloric acid (27ml of a 28X solution) and ice (150g). The mixture vas alloved to stand for half an hour and the mixture vas then added to a mixture of 2-benzylphenol (24g), 4.7H aqueous sodium hydroxide (150ml) and ice (150g) vhilst maintianing the temperature belov 5C. The mixture vas stirred for one hour, sodiu~ dithionite (58.8g) vas added and the mixture slovly heated to 70C. The reaction mixture vas then alloved to cool to ambient temperature to give a precipitate vhich vas collected by filtration to give a solid (23.47g). To a solution of this solid (20g) in water (150ml), propionic anhydride (32.5g) vas added and the resulting solution heated on a steam bath for 2.5 hours. The solution vas alloved to cool to ambient temperature and to stand overnight. The mixture was then extracted vith ethyl acetate (lOOml). The ethyl acetate extract vas vashed vith 2N aqueous hydrochloric acid (2 x lOOml), saturated aqueous sodium hydrogen carbonate solution (3 x lOOml) and vater (lOOml), dried (hgS04) and evaporated to give a 2-benzyl-4-propionamidophenol as a tarry oil (120.72g); NnR~CD30D]:
1.15(3H,t), 2.30(2H,q), 3.9(2H,s), 6.75(1H,d) and 7.05-7.3(7H,m).

~AnPL~s 22-64 Using a similar procedure to that described in Example 1 (vith exceptions as noted) the following compounds of formula 1 (in which A
and B are as indicated below) were prepared from the corresponding compounds of formula 2 (in which Z is bromo unless indicated wo 94,254~16 0 ~ ~ i 62 - ~CT/GB94/009lU

othervise) and 3-ethynyl-3-hydroxyquinuclidine. Vhere compounds of formula 2 are not commercially available preparative details are given.

E~hrLe 22 A , H, B = C~2CH2CO2 Purified by flash column chromatography on silica gel using lOX methanol in dichloromethane as eluent, folloved by recrystallisation from ethyl acetate to give the title compound as a solld, m.p. 142.2C; NHR: 1.5(3H,t), 1.30(1H,m), l.S9(1H,m), 1.88(2H,m), 2.62(2H,t), 2.72(4H,m), 2.82(2H,t), 3.05(1H,m), 3.31(1H,s), 4.03(2H,q), 5.51(1H,s), 7.20(2H,d) and 7.29(2H,d).
The compound of formula 2 (Z . trifluoromethylsulphonyloxy), m/z 328(h+H), used as starting material vas prepared using an analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-l(3-allyl-4-hydroxy)phenyllpropionate.

~AnPLE 23 ~ , allyl, B , CH2CH2CO2ne Purified by flash chromatography on silica gel using lOX
methanol in dichloromethane as eluent, to give the title compound as a solid, m.p. 63-65C, NHR(CDC13): 1.44(1H,m), 1.68(1H,m), 2.10(4H,m), 2.62(2H,t), 2.86(6H,m), 3.08(1H,d), 3.32(1H,d), 3.50(2H,d), 3.68(3H,s), 5.05(2H,m), 5.96(1H,m), 7.00(2H,m) and 7.33(1H,d).
The compound of formula 2 (Z = trifluoromethylsulphonyloxy), m/z 354(h+H), used as starting material vas prepared using an analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-l(3-allyl-4-hydroxy)phenyllpropionate.

E~AnrLE 24 ~ ~ H, B = rU-CUCO2Et Purified by crystallisation from ethyl acetate to give the title compound as a solid, m.p. 180.7C, NHR: 1.27(3H,t), 1.38(1H,m), 1.65(1H,m), 1.93(3H,m), 3.05(7H,m), 4.20(2H,q), 5.62(1H,s), 6.63(1H,d), 7.42(2H,d), 7.63(1H,d) and 7.70(1H,d).
The compound of formula 2 (Z=trifluoromethylsulphonyloxy), m/z 326(H+H), used as starting material was prepared using an W O 941254S9 216 ~ 7 ~ 5 ~CT/GB94/00910 analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-l(3-allyl-4-hydroxy)phenyllpropionate.

E~A~PLE 25 ~ - allyl, B ~ cr ~R~O2Et Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v) mixture of ethyl acetate/methanol as eluent, folloved by trituration with diethyl ether to give the title compound as a solid, m.p. 141.4C; NMR: 1.30(4H,m), 1.60(1H,m), 1.90(3H,m), 2.98(6H,m), 3.52(2H,d), 4.20(2H,q), 5.07(2H,m), 5.61(1H,s), 5.90(1H,m), 6.60(1H,d), 7.39(1H,d) and 7.60(3H,m).
The compound of formula 2 (Z . trifluoromethylsulphonyloxy), m/z 366(H+H), used as starting material was prepared using an analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate from ethyl 3-[(3-allyl-4-hydroxy)phenyllpropionate.

E~A~rLE 26 ~ - allyl, B ~ (C~2)3CO2he Obtained as a solid, m.p. 34-35C, N~R(CDC13): 1.43(1H,m), 1.65(1H,m), 2.01(4H,m), 2.30(2H,t), 2.61(2H,t), 2.85(4H,m), 3.05(1H,d), 3.32(1H,d), 3.67(3H,s), 5.04(2H,m), 5.97(1H,m), 6.97(2H,m) and 7.31(1H,m).
The compound of formula 2(Z = trifluoromethylsulphonyloxy), m/z 368(H+H), used as starting material was prepared from the methyl ester of 4-(4-hydroxyphenyl)butanoic acid using a method analogous to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.

E~nPLE 27 ~ = allyl, B = (C~2)4CO2~e Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v) mixture of ethyl acetate/methanol as eluent to give the title compound as a solid, m.p. 35-37C; NHR(CDC13): 1.44(1H,m), 1.70(5H,m), 2.02(3H,m), 2.31(2H,t), 2.60(2H,t), 2.86(4H,m), 3.05(1H,d), 3.33(1H,dd), 3.50(2H,d), 3.67(3H,s), 5.03(2H,m), 5.95(1H,m), 6.97(2H,m) and 7.31(1H,d).

21~79~

The compound of formula 2 (Z = trifluoromethylsulphonyloxy), m/z 382(H+H), vas prepared from methyl 5-(4-hydroxyphenyl)pentanoate using a method analogous to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-propionate.

ESAnPLE 28 A allyl, B ~ CH2C~2CO2C~(~e)Et Purified by flash chromatography on silica gel us~ng a 9:1 (v/v) mixture of dichloromethane/methanol as eluent to give a solid, m.p. 49-51C; N~R(CDC13): 0.86(3H,t), 1.15(3H,d), 1.55(4H,m), 2.05(3H,m), 2.58(2H,t), 2.86(6H,m), 3.06(1H,d), 3.34(1H,d), 3.51(2H,d), 3.82(1H,m), 5.05(2H,m), 5.97(1H,m), 7.01(2H,m) and 7.32(lH,d).
The compound of formula 2(Z ~ trifluoromethylsulphonyloxy), (H+H) = 396, used as starting material vas prepared by uslng a method analogous to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.

E~A~rLe 29 ~ - allyl, B . (C~2)2C02C~2c02~
Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v) mixture of ethyl acetate/methanol as eluent to give a solid, m.p. 73-75C; NnR(CDC13): 1.42(1H,m), 1.67(1H,m), 2.01(3H,m), 2.33(1H,m), 3.03(1H,d), 3.32(1H,dd), 3.50(2H,d), 3.75(3H,s), 4.61(2H,s), 5.04(2H,d), 5.95(1H,m), 7.02(2H,m) and 7.33(1H,d).

~2A~rLF 30 ~ - allyl, B - (CH2)2CO2(CH2)2O
Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v) mixture of ethyl acetate/methanol as eluent to give an oil, NnR(CDC13): 1.44(1H,m), 1.69(1H,m), 2.06(3H,m), 2.62(2H,t), 2.87(6H,m), 3.10(1H,m), 3.35(4H,m), 3.52(4H,m), 4.21(2H,m), 5.04(2H,m), 5.95(1H,m), 7.02(2H,m) and 7.32(1H,d).

L~ 31 ~ = H, B = OCH2C~2OCH2 Purified by flash chromatography on silica gel using 10Z
methanol in dichloromethane containing 1% ammonia (density, 0.88g/cm3) as eluent to give a gum, NHR(ICD312S0): 1.5-1.7(3H,m), 1.9-2.1(2H,m), W O 94/25459 2 ~ ~ ~ 7 ~ ~ PCT/GB94/00910 2.8-3.65(6H,m), 3.3(3H,s), 3.3-3.4(1H,m), 3.6-3.68(2H,m), 4.05-4.13(2H,m), 6.9(2H,d) and 7.32(2H,d).

~A~rL~ 32 A , allyl, B - OO2CH2C~2OCB3 Purified by flash chromatography on silica gel using lOZ
methanol in dichloromethane containing lX am~onia (density, 0.88g/cm3) as eluent to give a solid, m.p. 90-92C, NHR: 1.21-1.41~1H,m), 1.50-1.69(1H,m), 1.75-2.02(3H,m), 2.68(4H,t), 2.80-3.15(2H,q), 3.30(3H,s), 3.53-3.70(4H,m), 4.35-4.45(2H,m), 5.00-5.16(2H,m), 5.67(1H,s), 5.87-6.10(1H,m), 7.50-7.57(1H,d) and 7.77-7.85(2H,m).
The compound of formula 2 (Z ~ trifluoromethylsulphonyloxy) used as starting material was prepared as follows.
Anhydrous potassium carbonate (55g) in acetone (400ml) and allyl bromide (41.5ml) were added to a stirred solution of methyl 4-hydroxybenzoate (60.8g). The mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, filtered and the residue washed with ethyl acetate. The flltrates and vashings were combined, evaporated and the residue dissolved in dichloromethane. The organic phase was washed vith lH aqueous sodiu~
hydroxide (2 x 75ml), water, brine and dried (HgS04). Evaporation gave methyl 4-allyloxybenzoate as an oil (76.4g) which was used without further purification.
A mixture of methyl 4-allyloxybenzoate (1.92g), sodium cyanide (50mg) and 2-methoxyethanol (20ml) was heated at reflux for 24 hours. The mixture was evaporated to give an oil which was partitioned between dichloromethane and water. The organic phase was separated, washed with brine, dried (HgS04) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of pentane/ethyl acetate as eluent to give 2-methoxyethyl 4-allyloxybenzoate (1.7g) as an oil; NHR(CDC13):
3.44(3H,s), 3.72(2H,t), 4.44(2H,t), 4.55-4.64(2H,m), S.27-5.48(2H,m), 5.96-6.14(1H,m), 6.93(2H,d) and 8.01(2H,d); m/z237(H+H).
2-methoxyethyl 4-allyloxybenzoate (1.7g) was heated at 250-260C for 0.5 hour and the crude product was purified by flash column chromatography on silica gel using 3:2 (v/v) mixture of pentane/ethyl acetate as eluent to give 2-methoxyethyl 216U ~
W O 94/254~9 PCT/GB94/00910 3-allyl-4-hydroxybenzoate as an oil (1.36g); NHR(CDC13): 3.42(2H,d), 3.44(3H,s), 3.74(2H,t), 4.44(2H,q), 5.08-5.20(2H,m), 5.89-6.10(1H,m), 6.02(1H,s), 6.81(1H,d) and 7.77-7.85(2H,m); m/z237(H+H).
The triflate vas prepared using trifluoromethane 5lllphonic anhydride using the procedure described in Example 1 for the preparation of 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-propionate. There vas thus obtained 2-allyl-4-methoxyethoxy-carbonylphenyltrifluoromethane sulphonate as an oil; NnR(CDC13):
3.42(3H,s), 3.47-3.57(2H,d), 3.72(2H,t), 4.48(2H,t), 5.07-5.25(2H,m), 5.80-6.05(1H,m), 7.30-7.40(1H,d) and 7.95-8.08(2H,m); m/z 369(h+H).

~A~rLE 33 ~ ~ H, B ~ OCHzCH2SC~3 Purified by triturating vith diethyl ether, folloved by recrystallisation from acetonitrile to give a solid, m.p. 154-155C, N~R: 1.2-1.4(1H,m), 1.5-1.6(1H,m), 1.8-2.0(3H,m), 2.15(3H,s), 2.68(4H,t), 2.7-2.9(3H,m), 3.05(1H,d), 4.17(2H,t), 6.92(2H,d) and 7.32(2H,d).
The compound of formula 2 (Z . bromo) vas prepared as follovs.
Diethyl azodicarboxylate (13.4g) vas added over a period of 20 minutes to a stirred solution of 4-bromophenol (12g), 2-methylthioethanol (6.4g) and triphenylphospine (18.2g) in tetrahydrofuran (250ml) at -5C under an atmosphere of argon. The mixture vas stirred at ambient temperature for 1 hour and the solvent vas then removed by evaporation. The residue vas partitioned betveen dichloromethane (150ml) and vater (150ml). The aqueous phase vas separated and extracted vith dichloromethane (150ml). The dichloromethane extracts vere combined, vashed vith vater (2 x lOOml), dried (hgS04) and evaporated. The residue vas dissolved in a boiling mixture of toluene (50ml) and n-heptane (50ml). The solution vas chilled and the precipitated triphenylphosphine oxide removed by filtration. The filtrate vas evaporated and purified by medium pressure chromatography on silica gel using a 1:1 (v/v) mixture of toluene/n-heptane as eluent to give l-(4-bromophenoxy)-2-methyl-thioethane as an oil (10.2g); NnR(CDC13): 2.2(3H,s), 2.88(2H,t), 4.12(2H,t), 6.77(2H,d) and 7.37(2H,d).

W O 94/254~9 ~ ~ ~ 7 9 5 ~A~PL~ 34 ~ - H, B - CH2OCH2OCH3 Purified by triturating with diethyl ether, folloved by recrystallisation from acetonitrile, to give a solid, m.p. 148-150C;
N~R: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.75(4H,t), 2.75-2.9(1H,d), 3.0-3.1(1H,d), 3.3(3H,s), 4.5(2H,s), 4.65(2H,s), 5.5(1H,s) and 7.23-7.45(4H,dd).
The compound of formula 2 (Z = bromo) was prepared as folloYS.
Dimethoxymethane (80ml) and phosphorous pentoxide (40g) were added to a solution of 4-bromobenzyl alcohol (3.74g) in dry dichloromethane (80ml). The resultant slurry was stirred for one hour at room temperature and was then added to a cooled saturated sodium carbonate solution (600ml). The mixture was extracted with ether (3 x 200ml). The organic extracts vere combined, washed with water (25ml), brine (25ml), dried with (ngS04) and evaporated.
The residue was purified by vacuum flash chromatography on silica gel (herck 7736) using 50Z toluene/hexane as eluent to give 4-bromobenzyloxymethoxymethane as a colourless oil 2.6g. NMR: (CDC13):
3.4(3H,s), 4.5(2H,s), 4.7(2H,s), 7.2-7.3(2H,d) and 7.4-7.5(2H,d).

~S~rLe 35 ~ ~ allyl, B - (C~2)3OC~3 Purifled by flash chromatography on silica gel using 5X
methanol in dichloromethane containing 0.5X a~monia (density, 0.88g/cm ) as eluent to give an oil, NhR: 1.3-1.5(1H,m), 1.55-1.7(1H,m), 1.7-1.85(2H,m), 1.85-2.05(3H,m), 2.55-2.65(2H,t), 2.7-2.9(4H,m), 2.9-3.0(1H,d), 3.1-3.2(1H,d), 3.2(3H,s), 3.25-3.35(2H,t), 3.45-3.5(2H,d), 5.0-5.1(2H,m), 5.7(1H,s), 5.9-6.1(1H,m), 7.0-7.1(2H,d) and 7.2-7.3(1H,d).
The compound of formula 2 (Z = trifluoromethylsulphonyloxy) used as starting material was prepared as follows.
Powdered potassium carbonate (4.14g) and allyl bromide (3.99g) were added to a stirred solution of 3-(4-hydroxyphenyl)propanol (4.56g) in acetone (15ml) under an atmosphere of argon. The mixture heated at reflux for 20 hours.
After cooling to ambient temperature the solid potassium bromide was 21607~

renoved by filtration and Yashed Yith ether. The flltrate and vashings vere combined, Yashed Yith 2~ aqueous sodium hydroxide (2 x 20nl), vater (1 x 20ml), brine (20ml), dried (~gS04) and evaporated.
The residue vas purified by vacuum flash chromatography on silica gel (nerck 7736) using toluene as eluent to give 3-(4-allyloxyphenyl) propanol as a colourless oil (4.6g). NHR(CDC13): 1.3(1H,s), 1.8-2.0(2H,m), 2.6-2.7(2H,t), 3.6-3.7(2H,t), 4.45-4.55(2H,n), 5.2-5.5(2H,m), 5.95-6.15(1H,m), 6.8-6.9(2H,d) and 7.05-7.15(2H,d).
Thlonyl chloride (2 d ) vas added dropvise to a solution of 3-(4-allyloxyphenyl)propanol (4.7g) in toluene (50ml) contaln1ng pyridine (2.5ml). The reactlon mixture Yas stirred for 16 hours at room temperature and Yas then added to ~ater (80ml). The mixture Yas extracted Yith toluene (3 x 50ml), washed Yith vater (20ml), brine (20ml) dried (HgS04) and evaporated.
The residue vas purified by vacuum flash chromatography on silica gel (~erck 7736) using toluene as eluent to give, 3-(4-allyloxyphenyl)propyl chloride (S.lg); NnR(CDC13): 1.9-2.1(2H,m), 2.6-2.7(2H,t), 3.85-4.1(2H,m), 4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.9-6.2(1H,m), 6.8-6.9(2H,d) and 7.0-7.1(2H,d).
A mixture of 3-(4-allyoxyphenyl)propyl chloride (6.1g), dimethyl formamide (50ml), dibromomethane (25ml) and sodium bromide (3.28g) vas heated for 16 hours at 100C. The mixture vas poured into Yater (20ml) and extracted Yith ether (3 x 50ml). The organic extracts Yere combined, ~ashed Yith ~ater (20ml), brine (20ml), dried (ngS04) and evaporated. The residue Yas purified by vacuum flash chromatography on silica gel (~erck 7736) using 5Z ethyl acetate in hexane as eluent to give 3-(4-allyloxyphenyl)propyl bromide as a colourless oil (4.0g); NnR(CDC13): 2.0-2.2(2H,m), 2.65-2.8(2H,t), 3.3-3.4(2H,t), 4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.9-6.2(1H,m), 6.8-6.9(2H,d) and 7.1-7.2(2H,d).
3-(4-allyoxyphenyl)propyl bromide (4.0g) ~as added drop~ise to a cooled solution of methanol (50ml) and mercury II perchlorate prepared from mercury II oxide (3.39g) and 60% perchloric acid (4.71ml). The mixture Yas stirred for 16 hours at room temperature.
Saturated brine (80ml) was added and the mercury salts ~ere removed by filtration and the residue washed ~ith ether (30ml). The aqueous W 0 94125459 21 ~ ~ 7 9 ~ PCT/GB94100910 layer from the filtrate vas separated and further extracted vith ether (3 x lOOml). The organic extracts vere combined, were vashed vith vater (2 x 20ml), brine (1 x 20ml), dried (ngS04) and evaporated.
The residue vas purified by flash chromatography on silica gel using 5Z ethyl acetate in toluene as eluent to give 3-(4-allyloxyphenyl-1-methoxypropane as a colourless oil (1.6g) NMR(CDC13): 1.8-2.0(2H,m), 2.6-2.7(2H,t), 3.3-3.5(5H,m), 4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.95-6.15(1H,m), 6.8-6.9(2H,d) and 7.05-7.15(2H,d).
The 3-(4-allyloxyphenyl)-1 methoxypropane was heated at 200C for 2 hours under an atmosphere of argon. The product vas dlssolved in ether and extracted vith 2n aqueous sodium hydroxide (4 x 20 d ). The aqueous extracts vere combined, and acidified vith 2H
aqueous hydrochloric acid. The mixture vas extracted vith ether (2 x 3001), the ether extracts vere combined, vashed vith vater (lOml), brine (lOml), dried (hgS04) and evaporated to give 3-(2-allyl, 4-hydroxyphenyl), l-methoxypropane a colourless oil (940mg) vhich vas used vithout further purification; NHR(CDC13): 1.8-2.0(2H,o), 2.5-2.6(2H,t), 3.3-3.45(7H,t), 4.8(1H,s), 5.1-5.2(2H,m), 5.9-6.1(1H,m), 6.7-6.8(1H,d) and 6.9-7.0(2H,d).
Using a similar procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxy-phenyl)propionate but using 3-(2-allyl-4-hydroxyphenyl)-1-methoxypropane as starting material there vas obtained 2-allyl-4-(3-methoxypropyl)phenyl trifluoromethane sulphonate as a colourless oil; N~R(CDC13): 1.8-1.95(2H,m), 2.65-2.75(2H,t), 3.3-3.5(7H,m), 5.05-5.2(2H,m), 5.8-6.0(1H,m) and 7.0-7.3(3H,m).

~S~XPLL 36 ~ H, B CH2C~20CH2CH20cH3 Purified by flash chromatography on silica gel using 5%
methnol in dichloromethane containing 0.5X ammonia (density, 0.88g/cm ) as eluant to give a solid, m.p. 126-127C; N~R:
1.2-1.4(1H,m), 1.5-1.65(1H,m), 1.8-2.0(3H,m), 2.6-2.7(4H,t), 2.75-2.9(3H,m), 3.0-3.1(1H,d), 3.25(3H,s), 3.35-3.45(2H,m), 0 ~ 9 ~i W O 94/254~9 PCT/GB94/00910 3.45-3.55(2H,m), 3.55-3.65(2H,t), 5.55(1H,s), 7.2-7.3(2H,d) and 7.3-7.4(2H,d)-The compound of formula 2 (Z = bromo) used as starting material vas prepared as follovs.
4-bromophenethyl bromide (4.0g) was added in a dropvise manner to a cooled solution of methoxyethanol (50ml) and mercury II
perchlorate (prepared from 3.39g of mercury II oxide and 4.71g of 60Z
perchloric acid). The mixture vas stirred overnight at ambient temperature. Saturated brine (80ml) vas added, the mercury salts removed by filtration and vashed vith ether. The filtrate ~as extracted vith ether (3 x 100ml). The ether extracts vere combined, vashed vith vater (20ml), saturated brine (20ml), drled (hgS04) and evaporated. The residue vas purified by flash chromatography on silica gel using lOZ ethyl acetate in toluene as eluent to give 1-(-4-bromophenethyloxy)-2-methoxyethane (2.2g) as a colourless oil;
N~R(CDC13): 2.8-2.9(2H,t), 3.4(3H,s), 3.5-3.6(4H,m), 3.6-3.75(2H,t), 7.05-7.15(2H,d) and 7.35-7.45(2H,d).

PLe 37 ~ , H, B ~ CONHC~2C02ne Purified by flash chromatography on silica gel using lOZ
methanol in dichloromethane cont~in~ng lZ ammonia (density 0.88g/cm3) as eluent, folloved by recryst~ s~tion from ethanol to give a solid, m.p. 200-202C; NKR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.65(1H,s), 3.78(3H,s), 4.15(2H,s), 6.0(1H,s), 7.6(2H,d), 8.0(2H,d) and 9.12(1H,m).
The compound of formula 2 (Z , iodo) used as starting material vas prepared as follows:
Triethylamine (5.4ml) vas added to a solution of 4-iodobenzoyl chloride (5.06g) in dichloromethane (30ml) at 5C.
Glycine methyl ester hydrochloride (2.4g) vas then added to the reaction mixture and the mixture vas stirred at 5C for 2 hours. The mixture vas then stirred at ambient temperature overnight.
Dichloromethane (lOOml) vas added and the mixture vas washed vith vater (2 x lOOml), dried (~gS04) and evaported. The residue vas triturated vith pentane to give a solid vhich vas collected by filtration to give methyl 4-iodohippurate, m.p. 166-168C. NnR:

W O 94/25459 21~ a ~ ~ ~ PCT/GB94/00910 3.65(3H,s), 4.0(2H,d), 7.65(2H,m), 7.88(2H,m) and 9.0(1H,m); m/z 320(h+H)-PL~ 38 ~ H, B ~ CONH(CH2)2OC~3 Purified by flash chromatography on silica gel using 10Z
methanol in dichloromethane conta~ning 1~ ammonia (density, 0.88g/cm3) as eluent folloved by recrystallisation acetonitrile to give a solid, m.p. 165-167C; NHR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 3.3(2H,n), 3.45(5H,m), 5.64(1H,s), 5.65(1H,s), 7.45(2H,d), 7.82(2H,d) and 8.5(1H,m).
The compound of formula 2 (Z z iodo) used as starting material was prepared in an analogous manner to the compound of formula 2 in Example 37 in 89X yield, NnR: 3.3(3H,s), 3.45(4H,m), 7.62(2H,m), 7.85(2H,m) and 8.55(1H,m); m/z 306(H+H).

~AnPLC 39 A . R, B . CH2OCOCH( 3)2 Purified by flash chromatography on silica gel using a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent, folloved by trituration with acetonitrile to give a solid, NnR: 0.9(6H,d), 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.23(2H,d), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.1(2H,s), 5.65(1H,s), S.58(1H,s) and 7.37(4H,m).
The compound of formula 2 (Z = bromo) was prepared as follows.
A mixture of 4-bromobenzyl alcohol (lg) pyridine (0.6ml) and dichloromethane (40ml) was stirred under an atmosphere of argon at 3C
for O.S hours. Isovaleryl chlorile (0.73ml) was added to the reaction mixture dropwise over a period of S minutes. The mixture was stirred at 5C for 15 minutes, allowed to warm to ambient room temperature and stirred at ambient temperature for 1 hour. The reaction mixture was washed with 2n aqueous hydrochloric acid (20ml), water (20ml), and brine (20ml), dried (ngS04) and evaporated to give a colourless oil (1.4g). NHR: 0.9(6H,d), 2.0(2H,m), 2.2(2H,d), 5.05(3H,m), 7.35(2H,m) and 7.6(2H,m); m/z 272 (H+H).

2160~

PL~ 40 ~ - ~, B = O(C~2)2CN
Triturated with a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine to give a solid, NhR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.65(1H,s), 2.99(3H,t), 4.2(3H,t), 5.5(1H,s), 6.95(2H,s) and 7.35(2H,s).
The compound of formula z (Z = iodo) used as startlng material was prepared as follovs.
A 40X solution of benzyltrimethyl ammonium hydroxlde in vater (1.2ml) was added to a stirred solution of 4-iodophenyl (4g) in acrylonitrile (lOml) whilst under an atmosphere of argon. The temperature of the reaction mixture vas raised to 80C, gradually over 2 hours and was then heated at reflux for 2 days. The reaction mixture vas cooled to ambient temperature, diluted ~ith toluene (lOOml) and evaporated. The residue vas partitioned betveen lh aqueous sodium hydroxide (20ml) and ether (30ml). The aqueous phase vas separated and extracted ~ith ether (2 x 30ml). The ether extracts were combined, wa~hed vith water (20ml), brine (20ml), dried (hgS02) and evaporated to give a solid (1.6g) ~hich ~as used without further purification.

~ZAnPL~ 41 A . CBO, B - OCB2C~20C~3 Obtained as a solid, m.p. 116-118.5C; NhR(CDC13):
1.45(1H,m), 1.70(1H,m), 2.05(3H,m), 2.84(4H,t), 3.09(1H,d), 3.3(1H,d), 3.45(3H,s), 3.76(2H,m), 4.18(2H,m), 7.15(1H,dd), 7.48(2H,m) and 10.43(1H,s).
The compound of formula 2 (Z = trifluoromethylsulphonylloxy) used as starting material was prepared as follows.
Bromoethylmethyl ether (105.7g) was added to a stirred suspension of hydroquinone monobenzylether and unhydrous potassium carbonate (84.5g) in N,N-dimethylformamide (250ml). The reaction mixture was heated at 90C for 18 hours. The reaction mixture was allowed to cool to ambient temperature and the mixture filtered. The filtrate was dissolved in water (750ml) and the aqueous mixture was extracted with ethyl acetate (5 x 150ml). The ethyl acetate extracts were combined, washed with water (3 x lOOmls), brine (200mls), dried W O 94/25459 21~ O ~ ~ a PCT/GB94/00910 (~gS04) and evaporated to give 1-(benzyloxy)-4-(2-methoxyethoxy)-benzene (102.4g) as a solid; NhR: 3.3(3H,s), 3.61(2H,m), 4.0(2H,m), 5.02(2H,s), 6.9(4H,m) and 7.4(5H,m) and m/z 259(~+H).
~ mixture of 1-(benzyloxy)-4-(2-methoxyethoxy)ben7ene (180g), ethanol (2000ml) and palladium on carbon catalyst (20g) was stirred under an atmosphere of hydrogen, at room temperature and atoospheric pressure. After the theoretical quantity of hydrogen had been consumed, the reaction mixture vas filtered. The filtrate vas evaporated to give a solid Yhich vas crystallised from a mixture of ethyl acetate and n-hexane to give 4-(2-methoxyethoxy)phenol as a solid (94.7g) m.p. 97.9C; microanalysis, found: C, 64.3Z; H, 7.4Z;
CgH1203 requires: C, 64.3Z; H, 7.2Z; NhR: 3.35(3H,s), 3.6(2H,m), 3.95(2H,m), 6.7(4H,m) and 8.9(1H,s); mJz 169(H+H).
A solution of 4-(2-methoxyethoxy)phenol in toluene (350ml) was added to a solution of magnesium methoxide in methanol (8X by veight solution, 331mls), under an atmosphere of argon. The reaction mixture Yas heated at reflux for 2 hours. Toluene (350mls) vas added and the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92-C. A mixture of paraformaldehyde in toluene (300ml) vas added to the reaction mixture and the reaction mixture vas heated at reflux for 3.5 hours. The mixture vas cooled to ambient temperature and then stirred at ambient temperature for 18 hours. The reaction mixture vas diluted Yith toluene (400ml), washed vith 2h aqueous hydrochloric acid (2 x 150ml) and Yater (to pH 1).
The residue vas distilled under vacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35g), bp 104-130C IO.Olmm Hg]; NHR(CDC13): 3.45(3H,s), 3.75(2H,m), 4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and 10.63(1H,s); m/z 197(H+H).
Trifluoromethyl sulphonic anhydride (3.88ml) Yas added dropvise over a period of 10 minutes to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (4.11g) and 2,6-dimethylpyridine (2.67ml) in dichloromethane (20ml) at 0C under an atmosphere of argon. After stirring at room temperature for 16 hours, the mixture was added to ice (1OOg). The organic phase vas separated, washed with 5% aqueous sodium carbonate solution (2 x 10ml), dried (HgS04) and evaporated tO give an oil vhich was purified 2 1 ~

by flash column chromatography on silica gel using dichloromethane as eluent to give 2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxy)-benzaldehyde (2.2g) as an oil; NnR(CDC13): 3.45(3H,s), 3.78(2H,m), 4.19(2H,m), 7.3(2H,m), 7.48(1H,d) and 10.23(1H,d); m/z 329(H+H).

~AnPLL 42 ~ allyl, B . OC8(C83)C02C~3 Purified by flash chromatography on sillca gel using a 90:09:01 (v/v/v) mixture of ethyl acetate/methanol/ammonia (density, 0.88g/cm3) as eluent to give an oil, NHR: (CDC13) 1.3-l.5(lH,m), 1.55-1.76(4H,m), 1.9-2.5(3H,m), 2.7-3.0(4H,m), 3.0-3.2(1H,d), 3.2-3.4(1H,dd), 3.4-3.5(2H,d), 3.7-3.8(3H,ms), 4.7-4.8(1H,d), 5.0-5.15(2H,m), 5.8-6.05(1H,m), 6.6-6.8(2H,m) and 7.3-7.4(1H,d).

E~nPL~ 43 ~ ~ allyl, B ~ (CH2)2CO2He Obtained as a gum, NHR: 1.2-1.5(5H,m), 1.5-1.9(3H,m), 1.9-2.15(4H,m), 2.2-2.4(2H,t), 2.5-2.65(2H,t), 2.7-3.0(4H,m), 3.0-3.1(1H,d), 3.3-3.4(1H,dd), 3.45-3.55(2H,d), 3.65(3H,s), 5.0-5.1(2H,m), 5.9-6.1(1H,m), 6.9-7.0(2H,m) and 7.3-7.4(1H,d).
The compound of formula 2 (Z trifluoromethylsulphonyloxy) used as startlng material vas prepared in an analogous ~anner to the preparation of ethyl 3-(3-allyl-4-trifluoromethyl-sulphonyloxyphenyl)propionate described in Example 1.

~A~PL~ 44 ~ ~ allyl, B . (C82)2 C2(C~2)5 3 Purified by chromatography on alumina (Fluka 507C) using a 19:1 (v/v) mixture of ethyl acetate/methanol as eluent to give a solid, m.p. 39-41C, NHR(CDC13): 0.90(3H,t), 1.30(6H,s), 1.42(1H,m), 1.61(3H,m), 2.00(3H,m), 2.26(2H,m), 2.58(2H,t), 2.86(6H,m), 3.05(1H,d), 3.30(1H,d), 3.50(2H,d), 4.04(2H,t), 5.04(2H,m), 5.95(1H,m), 7.00(2H,m) and 7.31(4H,d).

~SAnPL~ 45 ~ = CH2CO2Lt, B = H
Purified by crystallisation from acetonitrile to give a solid, m.p. 137.5-138.5C; NHR: 1.2(3H, t), 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.7(4H, m), 2.8(1H, d), 3.1(1H, d), 3.8(2H, s), 4.1(2H, q), 5.6(1H, s) and 7.2-7.4(4H, m).

WO 94/25459 21~ PCT/GB94/00910 The compound of formula 2 (Z = iodo) used as starting material vas prepared as follovs.
A solution of 2-(2-iodophenyl)acetonitrile (2.82 g) in a mixture of 1:1 (v/v) ethanol/vater (70 ml) vas treated vith sodium hydroxide (2.4 g) and stirred at reflux for 4 hours. The resultant solution Yas cooled to ambient temperature, concentrated to 30 ml, diluted vith vater (100 ml) and ~ashed vith ethyl acetate (2 x 100 ml). The organic layers vere combined and extracted vith 2H aqueous sodium hydroxide solution (100 ml). The aqueous layer vas acldlfled to pH 1 vith concentrated hydrochloric acid and filtered. The solid collected vas vashed vith vater and vacuum drled to glve 2-(2-iodophenyl)acetic acid (1.45 g) as a solid, m.p. 110-113C;
microanalysis; found: C, 36.9; H; 2.7X; C8H7I02 requires: C, 36.7; H, 2.7X; NHR: 3.7(2H, s), 7.0(1H, m), 7.4(2H, m), 7.8(2H, d); 12.5(1H, br s) .
Extractlon of the acidic aqueous layers vith dichloromethane gave a further portion of the same product (0.5 g), >9OX pure by N~R.
A solutlon of 2-(2-lodophenyl)acetlc acld ln ethanol (20 ml) vas treated vith concentrated sulphurlc acid (0.5 ml) and heated at reflux for 18 hours. The resultant solution ~as cooled to amblent temperature, concentrated to 5 ml and dlluted vith saturated aqueous sodium hydrogen carbonate solutlon (30 ml). Extraction vlth ethyl acetate (2 x 50 ml) gave an oll (450 mg) vhich vas purified by chromatography on silica gel eluting vith-20Z ethyl acetate in hexane to glve ethyl 2-(2-lodophenyl)acetate as a solld, m.p. 40.5-41.5C;
NHR: 1.2(3H, t), 3.8(2H, s), 4.1(2H, q), 7.0(1H, m), 7.4(2H, m) and 7.9(1H, d).

e~A~PL~ 46 ~ = C~2SLt, B ~ H
Purified by chromatography on silica gel (Varian Bond-Elut Sl silica gel) using a gradient of methanol in dichloromethane containing 1% ammonia (density, 0.88 g/cm3) as eluent, folloved by crystallisation from acetonitrile, to give a solid, m.p. 126-127.5C;
NnR: 1.2(3H, t), 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.4(2H, q), 2.7(4H, m), 2.9(1H, d), 3.1(1H, d), 3.9(2H, s), 5.6(1H, s) and 7.2-7.4(4H, m).

2:i 6 3 ~ ~ ~
W O 94/2~4~9 PCT/GB94/00910 The compound of formula 2 (Z = iodo) used as a starting material ~as prepared using the procedures described for the preparation of the compound of formula 2 in Example 47 except the reaction vas carried out on double the scale and ethanethiol (0.65 ml) and potassium carbonate (1.32 g) vere used in place of sodium methanethiolate.
There vas thus obtained 2-ethylthiomethyliodoben7~ne (1.98 g) as a colourless oil; NnR: 1.2(3H, t), 2.4(2H, q), 3.8(2H, s), 7.0(1H, m), 7.4(2H, m) and 7.9(1H, m).

~S~PLe 47 ~ , CH2SHe, B - H
Purified by trituratlon vith acetonitrile to give a solid, m.p. 118-119.5C, NnR: 1.2(1H, m), 1.4(1H, m), 1.7-1.8(3H, m), 1.8(3H, s), 2.5(4H, m), 2.7(1H, d) 2.9(1H, d), 3.6(2H, s), 5.4(1H, s) and 7.0-7.3(4H, m).
The starting material (Z - iodo) vas prepared as follovs.
A solution of 2-chloromethyliodobenzene (1.01 g) ln ethanol (15 ml) vas deoxygenated vith a stream of argon and vas then treated vlth sodium methanethiolate (336 mg) and sodium borohydride (182 mg).
The suspension vas stirred vlgorously at ambient temperature for 22 hours and vas then diluted vlth diethyl ether (40 ml), vashed vith vater (2 x 30 ml) and brine (30 ml). The aqueous layers vere back-extracted vith ether, the organic layers vere combined, dried (HgS04) and concentrated to give 2-methylthiomethyIiodobenzene (1.02 g) as a colourless oil (used in the next step vithout further purification); NHR: 2.0(3H, s), 3.8(2H, s), 7.0(1H, m), 7.4(2H, m)and 7.9(1H, d).

e2AnPL~ 48 ~ ~ allyl, B ~ C02(CH2)30CH2cH3 Purified by flash chromatography on silica gel using 10X
methanol in dichloromethane containing lZ ammonia (density, 0.88 g/cm ) as eluent to give a solid, m.p. 75-77C, NHR (CDC13):
1.20(3H,t), 1.34-1.53(1H, m), 1.53-1.80(2H, m), 1.90-2.15(5H, m), 2.75-3.06(5H, m), 3.06(1H, d), 3.32(1H, dd), 3.50(3H, q), 3.55(2H, t), 4.41(2H, t), 5.00-5.15(2H, m), 5.88-6.05(1H, m), 7.45(1H, d) and 7.78-7.90(2H, m).

WO 94/25459 ~ 1 ~ 0 7 ~ 5 PCT/GB94/00910 The compound of formula 2 (Z = trifluoromethylsulphonyloxy) vas prepared from 3-ethoxypropyl-4-allyloxybenzoate using the method described in Example 1 for the preparation of 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.
3-Ethoxypropyl-4-allyloxybenzoate was prepared as described in Example 32 but using 3-ethoxy-1-propanol instead of 2-nethoxyethanol. The product Yas an oil; NHR (CDCl3): 1.20(3H, t), 2.02(2H, quintet), 3.43-3.62(4H, m), 4.38(2H, t), 4.55-4.64(2H, m), 5.27-5.49(2H, m), 5.95^6.16(1H, m), 6.93(2H, d), 7.98(2H, d); m/Z 265 (H+H).

~A~PL~ 49 ~ ~ allyl, B ~ C~2C~2OOC~3 Purified by flash chromatography on silica gel using a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylad ne as eluent folloYed by trituration Yith diethyl ether to give a solid, 101-104C, NhR: 1.2-1.4 (lH, m), 1.5-1.7 (lH, m), 1.8-2.02 (3H, m), 2.1 (3H, s), 2.6-2.8 (8H, m), 2.82-2.92 (lH, d), 3.05-3.15 (lH, d), 3.45 (2H, d), 5.05 (2H, m), 5.55 (lH, s), 5.9 (lH, m), 7.05 (2H, m) and 7.25 (2H, m).
The compound of formula 2 (Z ~ trifluoromethylsulphonyloxy) Yas prepared in a similar manner to the compound of formula 2 described in Example 1. Thus, the process described in Example 1 was used to convert 4-(4-hydroxyphenyl)-2-butanone to 4-(4-allyloxyphenyl)-2-butan~ne which Yas obtained in 79Z yield as an oil; NMR: 2.1 (3H, s), 2.7 (2H, m), 2.85 (2H, m), 4.5 (2H, m), 5.25 (lH, m), 5.4 (lH, m), 6.0 (lH, m), 6.85 (2H, m) and 7.05 (2H, m).
In a similar manner to that described in Example 1, 4-(4-hydroxyphenyl)-2-butanone Yas converted to 4-(3-allyl-4-hydroxyphenyl)-2-butanone Yhich Yas obtained as an oil; N~R: 2.05 (3H, s), 2.65 (4H, m), 3.25 (2H, d), 5.0 (2H, m), 5.9 (lH, m), 6.65 (lH, d), 6.8 (2H, m) and 9.05 (lH, s).
In a similar manner to that described in Example 1, 4-(4-hydroxyphenyl)-2-butanone ~as converted to 4-(3-allyl-4-trifluoro- methylsulphonyloxyphenyl)-2-butanone in 80Z

2 ;1 ~ 0 ',' ~ ^~

yield, NHR: 2.15 (3H, s), 2.75 (2H, m), 2.9 (2H, m), 3.45 (2H, d), 5.1 (2H, m), 5.9 (lH, m), 7.15 (3H, m). m/z 337 (~+H).

e2A~PLe 50 ~ ~ allyl, B CO(CH2)2CO2et Purified by flash chromatography on silica gel uslng a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give an oil, NHR: 1.18 (3H, t), 1.2-1.4 (lH, m), 1.5-1.7 (lH, m), 1.8-2.02 (3H, m), 2.6-2.8 (4H, m), 2.82-2.92 (lH, d), 3.05-3.15 (lH, d), 3.22 (2H, m), 3.3 (2H, m), 3.6 (2H, d), 4.15 (2H, q), 5.1 (2H, m), 5.75 (lH, s), 6.0 (lH, m), 7.5 (lH, d) and 7.8 (2H, d).
The compound of formula 2 (Z = trifluoromethylsulphonyloxy) used as starting material ~as obtained as follows.
Sulphuric acid (98X, 1.0 ml) was added, dropvise, to a stirred solution of 4-(4-hydroxyphenyl)-4-oxo-butyric acid (5.0 g), in ethanol (50 ml). The resulting solution ~as then heated at S0C for 18 hours. The solvent ~as evaporated and the residue ~as dissolved in ethyl acetate. The mixture vas ~ashed ~ith saturated aqueous sodium bicarbonate solution, ~ater, dried (HgSO4) and evaporated to give ethyl 4-(4-hydroxyphenyl)-4-oxo butyrate as a solid (5.3 g), NhR: 1.15 (3H, t), 2.6 (2H, t), 3.2 (2H, t), 4.15 (2H, q), 6.85 (2H, m), 7.85 (2H, m) and 10.27 (lH, s).
Using a similar procedure to Example 1 but using ethyl 4-(4-hydroxyphenyl)-4-oxobutyrate there ~as thus obtained ethyl 4-(4-allyloxyphenyl)-4-oxobutyate (9OZ yield) as an oil; N~R ICDC131:
1.1 (3H, t), 2.65 (2H, t), 3.2 (2H, t), 4.15 (2H, q), 4.55 (2H, m), 5.3 (2H, m), 6.0 (lH, m), 6.9 (2H, m) and 7.9 (2H, m).
Using a similar procedure as example 1 but using the above as starting material there ~as thus obtained ethyl 4-(3-allyl-4-hydroxy- phenyl)-4-oxobutyrate (25% yield) as a solid;
N~R: 1.18 (3H, t), 2.55 (2H, t), 3.15 (2H, t), 3.35 (2H, m), 4.15 (2H, q), 5.05 (2H, m), 5.9 (lH, m), 6.9 (lH, m), 7.7 (2H, m) and 10.3 (lH, s) .
Using a similar procedure as example 1 but using the above as starting material there ~as obtained ethyl 4-(3-allyl-4-trifluoro-methylsulphonyloxyphenyl)-4-oxobutyrate (85% yield) after purification W O 94/25459 216 0 7 9 ~ PCT/GB94/00910 (column chromatography on silica using 50X ethyl acetate/pentane as eluent) as an oil; NnR: 1-15 (3H, t), 2.65 (2H, t), 3.32 (2H, m), 3.55 (2H, m), 4.07 (2H, q), 5.18 (2H, m), 5.95 (lH, m), 7.58 (lH, m), 8.05 (2H, m).

PL~ 51 ~ ~ allyl, B 5 COCH2C02et Purified by flash chromatograph on silica gel using a 80:20:2 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give an oil, NHR: 1.2 (3H, t), 1.2-1.4 (lH, m), 1.5-1.7 (lH, m), 1.8-2.02 (3H, m), 2.6-2.8 (4H, m), 2.82-2.92 (lH, d), 3.05-3.15 (lH, d), 3.55 (2H, d), 4.15 (4H, m), 5.1 (2H, m), 5.75 (lH, s), 6.0 (lH, m), 7.5 (lH, m) and 7.75 (2H, m).
The compound of formula 2 (Z=trifluoromethylsulphonyloxy) used as starting material vas obtained as follovs:
Dlethyl carbonate (50 ml) vas heated to reflux, under an atmosphere of argon. The heat source vas removed and freshly prepared sodium (3 g) vas added over a period of 20 minutes. The reaction temperature vas raised to reflux and a hot solution of 3-allyl-4-hydroxyacetoxyphenone (7.8 g) in diethyl carbonate (80 ml) vas added.
Ethanol produced (about 15 ml) during the reactlon vas removed at the elevated temperature of the reaction mixture together vlth some dlethyl carbonate. Dlethyl carbonate (150 ml) vas then added to the reaction mixture and the reactlon mixture heated at reflux for 2.5 hours.
The reaction mixture vas cooled to 30C and ice vater (50 ml) Yas added cautiously. The mixture vas carefully neutralized by addition of 3H aqueous hydrochloric acid (-40 ml) and the aqueous mixture vas extracted vith diethyl ether (3 x 50 ml). The organic extracts ~ere combined, dried (HgS04) and evaporated to give an oil, vhich vas purified using dry flash chromatography on 60H silica (Herck Art. No. 7736) using a mixture of ethyl acetate and toluene as eluent to give ethyl 4-(3-allyl-4-hydroxyphenyl)-3-oxo-propionate (7.2 g), NnR [CDCl31: 1.2 (3H, t), 3.4 (2H, d), 3.95 (2H, s), 4.2 (2H, q), 5.1 (2H, m), 6.0 (lH, m), 6-85 (lH, m) and 7.7 (2H, m); m/z = 249 (H+H).

2~l3i793 In an alternative procedure, triethylamine (0.28 ml) was added to an ice cooled solution of ethyl 4-(3-allyl-4-hydroxyphenyl)-3-oxo- propionate (O.S g), in dichloromethane (10 ml). The reaction mixture was stirred for 5 minutes and trifluoromethane sulphonic anhydride (0.34 ml) was then added in a dropvise manner. The reaction mixture vas stirred for lS
minutes.
The reaction mixture vas diluted vith dichloromethane (20 ml), vashed vith vater (10 ml), brine (10 ml), dried (HgS04) and evaporated to give an oil vhich vas purified by flash chromatography on sillca gel using toluene as eluent, to give a colourless oil (0.7 g). m/z = 381 (~+H).

PLL 52 ~ , ~, B - CH2C~2CN
Purified by flash chromatography on silica gel using a 80:20:2 (v/v/v) mixture of ethyl acetate/ethanol/triethylamlne as eluent to give a solid (0.13g), NHR: 1.2-1.4 (lH, m), 1.5-1.7 (lH, m), 1.8-2.02 (3H, m), 2.6-2.8 (4H, m), 2.75 (2H, m), 2.85 (2H, m), 2.82-2.92 (lH, d), 3.05-3.15 (lH, d), 7.25 (2H, d) and 7.33 (2H, m).
The compound of formula 2 (Z ~ trifluoromethylsulphonyloxy) used as starting material vas prepared as follows:
Uslng a slmllar procedure to Example 1, but uslng 3-(4-hydroxyphenyl)propionltrile (0.8 g), as the startlng material, vas thus obtalned 3-(4-trifluoromethylsulphonyloxyphenyl)propionitrile (1 g); NHR: 2.85 (2H, m), 2.95 (2H, m), 7.5 (4, m); m/z - 297 (~+NH4)-CH2C2CH2C~2C~3' B H
Obtained as a gum, NhR: 0.9(3H, t), 1.4(1H, m), 1.5-1.7(3H, m), 1.8-2.0(3H, m), 2.7(4H, m), 2.9(1H, d), 3.1(1H, d), 3.8(2H, s), 4.0(2H, t), 5.7(1H, s), 7.2-7.4(4H, m).
The starting material of formula 2 (Z = iodo) was prepared in a similar manner to the compound of formula 2 described in Example 54 except propan-1-ol (0.16 ml) was substituted for propan-2-ol.
There was thus obtained propyl 2-(2-iodophenyl)acetate (232 mg) as a W O 94/25459 21~ O $ ~ 5 PCTIGB94/00910 yellow oil; NHR: 0.9(3H, t), 1.6(2H, m), 3.8(2H, s), 4.0(2H, t), 7.0(1H, m), 7.4(2H, m), 7.9(1H, d).

~AnPL~ 54 ~ ~ CH2CO2CHne2, B - H
Purified by chromatography on silica gel (Varian Bond Elut Sl silica gel) using a gradient of methanol in dichloromethane containing lX ~mmonia (density 0.88 g/cm3) as eluent to give a gum, NHR: 1.2(6H, d), 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.7(4H, m), 2.9(1H, d), 3.1(1H, d), 3.8(2H, s), 4.9(1H, m), 5.6(1H, s), 7.2-7.4(4H, m).
The compound of formula 2 (Z - iodo) used as starting material was prepared as follows.
A solution of 2-(2-iodophenyl)acetic acid (0.50 g) and propan-2-ol (0.142 ml) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.458 g) with stirring at ambient temperature under an atmosphere of argon. After 18 hours the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3 x 50 ml) and brine. The aqueous layers were back-extracted with ethyl acetate (50 ml) and the organic layers were combined, dried (HgS04) and evaporated. The residue was purified by chromatography on silica gel (Varian Band Elut Sl silica gel) eluting with dichloromethane to give 2-propyl 2-(2-iodophenyl)acetate (232 mg) as a yellow oil, NHR: 1.2(6H, d), 3.8(2H, s), 4.9(1H, m), 7.0(1H, m), 7.4(2H, d) and 7.85(1H, d).

pL~ 55 ~ = allyl, ~ = C~2CH(C~3)CO2C~3 Purified by column chromatography on alumina (Fluka 507C
Neutral) using a 19:1 (v/v) mixture of ethyl acetate and methanol as eluent to give an oil; NHR(CDC13): 1.12(3H,d), 1.40-1.55(1H,m), 1.57-1.75(1H,m), 1.90-2.15(3H,m), 2.30(1H,bs), 2.57-2.76(2H,m), 2.78-3.02(5H,m), 3.06(lH,d), 3.31(lH,d.d), 3.49(2H,d), 3.62(3H,s), 4.98-5.11(2H,m), 5.87-6.02(1H,m), 6.97(2H,m) and 7.32(1H,d): m/z 368(H+H).
The compound of formula 2 ( Z = trifluoromethylsulphonyloxy) was prepared as follows.

~l~Oi~{~5 A solution of methyl trans 2-methyl-3-(4-hydroxyphenyl)-cinnamate (2.79g) (JA~ Chem. Soc. 72, 2619, 1950) in ethyl acetate (55ml) ~as hydrogenated at ambient temperature/atmospheric pressure over a 10Z palladium/carbon catalyst. The catalyst ~as reooved by filtration and the filtrate ~as evaported. The residue vas purified by flash-column chromatography on silica gel using a 7:3(v/v) mixture of hexane and ethyl acetate as eluent to give methyl 2-methyl-3-(4-hydroxyphenyl)propionate (2.45g) as a colourless oil:
NKR(CDC13): 1.15(3H,d), 2.63(2N,m), 2.92(lH,q), 3.60(3H,s), 5.05(1H,bs), 6.71(2H,d) and 7.00(2H,d).
Hethyl 2-methyl-3-(4-allyloxyphenyl)propionate m/z 235(H+H) vas prepared from methyl 2-methyl-3-(4-hydroxyphenylpropionate using the method described in Example 1 for the preparation of ethyl 3-(4-allyloxyphenyl)propionate. Hethyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate vas prepared from methyl 2-methyl-3-(4-allyloxyphenyl)propionate using the method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-hydroxyphenyl)-propionate. The product ~as isolated as an orange oil; N~R(CDC13):
1.13(3H,d), 2.40-2.73(2H,m), 2.92(1H,q), 3.37(2H,d), 3.63(3H,s), 4.91(1H,s), 5.03-5.18(2H,m), 5.89-6.10(1H,m), 6.70(1H,m) and 6.91(2H,m); m/z 235(H+H).
The method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate vas used to convert methyl 2-methyl-3-(3-allyl-4-hydro~h~n~l)propionate to methyl 2-methyl-3-(3-allyl-4-trifluoromethyl-sulphonyloxyphenyl)propionate: N~R(CDC13) 1.18(3H,d), 2.70(2H,m), 3.01(1H,m), 3.42(2H,d), 3.62(3H,s), 5.13(2H,m), 5.90(1H,m), 7.08(2H,m) and 7.16(lH,d), m/z 366(H+H).

Le 56 ~ ~ allyl. B ~ CH2CH2CO2CH2 2 3 Purified flash chromatography on silica gel using a 19:1 (v/v) mixture of ethyl acetate and methanol as eluent to give a solid, m.p. 70-72CC; NHR(CDC13): 1.37-1.52(1H,m), 1.60-1.78(1H,m), 1.93-2.18(3H,m), 2.62(2H,t), 2.76-2.98(6H,m), 3.02-3.17(1H,m), 3.28-3.41(4H, m+s), 3.45-3.60(4H,m), 4.21(2H,m), 4.98-5.10(2H,m), 5.88-6.02(1H,m), 6.98-7.06(2H,m) and 7.32(1H,d), m/z 398(H+H).

W O 94/25459 21~ 0 7 9 ~ PCT/GB94/00910 The compound of formula 2 (Z = trifluoromethylsulphenyloxy), was prepared as follows.
3-Allyl-4-hydroxyphenyl propionic acid (l.lg) was treated with 2-methoxyethanol (lOml) containing concentrated sulphuric acid (0.lml) for 5 hours at 100C. The methoxyethanol was evaporated and the residue treated with saturated sodium bicarbonate (25ml). The aqueous mixture vas extracted vith ether (3 x 25ml). The ether extracts were combined, washed vith saturated brine (1 x 25ml), dried (HgSO4) and evaporated. The residual oil was purified by flash colu~n chromatography on silica gel using a 4:1 (vtv) mixture of hexane and ethyl acetate to give methoxyethyl 3-(3-allyl-4-hydroxyphenyl)-propionate (915mg) as a pale yellov oil; NHR(CDCl3): 2.61(2H,t), 2.87(2H,t), 3.38(3H,s), 3.57(2H,t), 4.21(2H,t), 4.98(lH,s), 5.08-5.18(2H,m), 5.92-6.08(1H,m), 6.71(1H,m) and 6.93(2H,m): m/z 265(h+H).
The triflate was prepared as in Example 1 using methoxyethyl 3-(3-allyl-4-hydroxyphenyl)propionate in place of ethyl 3-(3-allyl-4-hydroxyphenyl)propionate.
Hethoxyethyl 3-(3-allyl-4-trifluoromethylsulphonyloxy-phenyl)propionate was obtained as an oil; NnR(CDCl3) 2.65(2H,t), 2.93(2H,t), 3.38(3H,s), 3.95(2H,d), 3.57(2H,m), 4.21(2H,m), 5.07-5.20(2H,m), 5.82-5.98(1H,m) and 7.15(3H,m).

EYAnPLe 57 A ~ allyl, B = CH20CH2C02ne Obtained as an oil, NnR(CDCl3): 1.33-1.50(1H,m), 1.57-1.75(1H,m), 1.95-2.15(3H,m), 2.25-2.60(1H,m, exchangeable) 2.74-3.00(4H,m), 3.08(2H,d), 3.32(1H,d.d), 3.52(2H,d), 3.75(3H,s), 4.10(2H,s), 4.60(2H,s), 5.06(2H,m), 5.95(lH,m), 7.18(2H,m) and, 7.38(1H,d); m/z 370(H+H).
The compound of formula 2 (Z = trifluoromethylsulphonyloxy), methyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-methyloxyacetate, was prepared as follovs. Allyl bromide (4.4g) was added to a stirred suspension of 4-hydroxybenzyl alcohol (4.34g) and potassium carbonate (5.00g) in butanone (40ml). The reaction mixture vas heated at reflux for 18 hours. The reaction mixture was cooled and then filtered. The filtrate was evaporated to give an oil which 21S;~ ~ 9`~

~as purifed by flash column chromatography on silica gel using a 4:1 (v/v) mixture of hexane and ethyl acetate as eluent to give 4-allyloxybenzyl alcohol (4.50g) as a pale yellov oil; NnR(CDC13):
1.81(1H,t), 4.48-4.65(4H,m), 5.22-5.48(2H,m), 6.05(1H,m), 6.90(2H,m) and ?.25(2H,m), m/z 164(h).
Sodium hydride (1.20g; 60Z dispersion in oil) was added over a period of 10 minutes to a stirred solution of 4-allyloxybenzyl alcohol (4.60g) in DhF (20ml) at 0C under an atmosphere of argon.
After 0.5 hours, a solution of methylchloroacetate (3.30g) ln DhY
(lOml) vas added over a period of 0.25 hours. The reaction mixture was stirred for 40 hours at ambient temperature. ~ater (300ml) vas added and the mixture extracted with ethyl acetate (3 x lOOml). The ethyl acetate extracts were combined, vashed uith brine (2 x lOOml), dried (hgS04) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of hexane/ethyl acetate to give 4-allyloxyphenylDethyloxy acetate (2.42g) as a colourless oil; NHR(CDC13): 3.75(3H,s), 4.07(2H,s), 4.52(4H,m), 5.36(2H,m), 6.10(1H,m), 6.88(2H,m) and 7.28(2H,m); m/z 236(H).
A mixture of methyl 4-allyloxyphenyl~ethyloxyacetate (2.00g) and diphenyl ether (14ml) was heated at 200C in an atmosphere of argon for 9 hours. The mixture was cooled to ambient temperature and purified by flash column chromatography on silica gel using a 4:1 (v/v) mixture of hexane and ethyl acetate as eluent to give methyl (3-allyl-4-hydroxyphenyl)methyloxyacetate (435mg) as a colourless oil;
NHR(CDC13): 3.38(2H,d), 3.75(3H,s), 4.07(2H,s), 4.52(2H,s), 5.12(2H,m), 6.00(1H,m), 6.78(1H,m) and 7.08(2H,m); m/z 236(h).
Trifluoromethane s~)lphonic anhydride (0.33ml) ~as added over a period of 0.1 hours to a stirred solution of the above phenol (414mg) in pyridine (2ml) at 0C under an atmosphere of argon. After 18 hours, water (30ml) was added. The aqueous phase was extracted with ethyl acetate (3 x 20ml). The ethyl acetate extracts were combined, washed with lH aqueous hydrochloric acid (3 x 20ml), brine (2 x 30ml), dried (hgS04) and evaporated. The residue was purified by flash column chromatography on silica gel using a 19:1 (v/v) mixture of hexane and ethyl acetate as eluent to give methyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)methyl oxyacetate W O 94/25459 21 fi 0 7 9 ~ PCT/GB94/00910 (437mg) as a colourless oil; NHR(CDC13): 3.45(2H,d), 3.78(3H,s), 4.12(2H,s), 4.60(2H,s), 5.14(2H,m), 5.90(1H,m) and 7.27(3H,m).

ESA~PLE 58 ~ - allyl, B ~ C82CH2CON(Et)2 Purified by flash chromatography on silica gel using a 90:9:1 (v/v/v) mixture of ethyl acetate/methanol/ammonia as eluent to give an oil; N~R(CDC13): 1.10(6H,t), 1.33-1.52(1H,m), 1.52-1.72(1H,m), 1.92-2.16(3H,m), 2.55(2H,m), 2.75-3.03(7H,m), 3.08-3.42(5H,m), 3.50(2H,d), 4.97-5.11(2H,m), 5.85-6.05(lH,m), 7.02(2H,m) and 7.32(lH,d), m/z 395(H+H).
The compound of formula 2 (Z s trifluoromethylsulphonyloxy)~
N,N-diethyl 3-(3-allyl-4-trifluromethylsulphonyloxy-phenyl)propiona~ide, used as starting vas prepared from N,N-diethyl 3-(4-hydroxyphenyl)propionad de using the procedure described in Exa~ple 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethyl-sulphonyloxyphenyl)propionate via the folloving intermediates a) N,N-diethyl 3-(4-allylo~her,~l)propionamide, a colourless oil; NHR(CDC13): 1.10(5H,m), 2.53(2H,m), 2.90(2H,m), 3.22(2H,q), 3.37(2H,q), 4.51(2H,d.t), 5.23-5.47(2H,m), 5.95-6.15(1H,m), 6.83(2H,m) and 7.12(2H,m), m/z 262(H+H).
b) N,N-diethyl 3-(3-allyl-4-hydroxyphenyl)propionamite, a pale yellov oil; NHR(CDC13): 1.10(6H, m), 2.55(2H,m), 2.88(2H,m), 3.22(2H,q), 3.38(4H,q), 5.06-5.20(2H,m), 5.61(1H,br.d), 5.90-6.10(1H,m), 6.7S(lH,m) and 6.97(2H,m), m/z 262(H+H).
c) N,N-diethyl 3-(3-allyl-4-trifluoromethyl sulphonyloxy-phenyl)prop~onamide, a pale yellov oil; m/z 394(H+H).

~SAnPL~ 59 ~ 8 C~2OCH2C_CCR3, B , H
Purified by chromatography on silica gel (Varian Bond Elut Sl silica gel) using a gradient of 0 to 5X methanol in dichloromethanol as eluent to give a gum, NHR(CDC13): 1.45(1H,m), 1.7(1H,m), 1.88(3H,t), 2.09(3H,m), 2.88(4H,m), 3.1(1H,d), 3.35(1H,d), 4.2(2H,q), 4.7(2H,s), 7.3(2H,m) and 7.42(2H,t); m/z 310 (H+H).
The compound of formula 2 (Z = iodo) used as starting material vas prepared in a similar manner tO the compound of formula 2 described in Example 60 but using 2-iodobenzyl chloride in place of 2160~9~

2-iodobenzyl alcohol and 2-butyn-1-ol in place of allyl bromide. The reaction mixture vas used without purification.

~2A~PL~ 60 ~ ~ CB2OCB2CHsCH2, B B
Purifled by chromatography on silica gel (Varlan Bond Elut S1 silica gel) using a gradient of 0 to 5Z mèthanol in dichloromethane as eluent to give a gum, NHR(CDCl3): 1.5(1H,m), 1.72(1H,m), 2.12(3H,m), 2.9(4H,t), 3.05(2H,m), 3.15(lH,d), 3.38(lH,d), 4.05(2H,m), 4.62(2H,s), 5.25(2H,m), 5.95(1H,m), 7.22(lH,t), 7.35(1H,t), 7.45(2H,q); m/z 298(H+H).
The compound of formula 2 (Z = iodo) was prepared as folloYs.
Sodlum hydride (220mg of 60Z dispersion in mineral oil) vas added to a stirred solution of 2-iodobenzylalcohol (1.17g) in dimethylformamide under an atmosphere of argon. Allyl bromide (520~1) was added to the stirred suspension and the mixture was stirred at ambient temperature for 16 hours and then heated at 60C for 2 hours.
The mixture was used without purification.

~SAXPL~ 61 ~ . CH2OCH2CH3, Purifed by chromatography on silica gel (Varian Bond Elut S1 silica gel) using a gradient of 0 to 5Z methanol in dichloromethane as eluent to give a gum, NNR(CDCl3): 1.25(3H,t), 1.45(1H,m), 1.7(1H,m), 2.08(3H,m), 2.85(4H,t), 3.1(1H,d), 3.33(1H,d), 3.59(2H,q), 4.65(2H,s), 7.2(1H,t), 7.32(1H,t), 7.42(2H,q); mtz 286 (H+H) The compound of formula 2 (Z = iodo) was prepared using the procedure described in Example 60 for the compound of formula 2 but using ethyl iodide in place of allyl bromide.
The reaction mixture was used without purification.

PL~ 62 ~ = CH2OCOCH2CH3' B = H
Purified by chromatography on silica gel (Varian Bond Elut S1 silica gel) using a 0 to SZ gradient of methanol in dichloroethane as eluent to give a gum; NHR(CDCl3): 1.16(3H,t), 1.45(1H,m), 1.69(1H,m), 2.0(3H,m), 2.4(2H,q), 2.87(4H,m), 3.07(1H,d), 3.84(1H d of d), 5.27(2H,d), 7.25-7.45(4H,m). m/z 314 (H+H).

W O 94/25459 ~ J ~ 5 PCT/GB94/00910 The compound of formula 2 (Z = iodo) was prepared as follovs.
Propionyl chloride (S05mg) vas added to a stirred solution of 2-iodobenzyl alcohol (1.17g) and pyridine (474mg) in dichloromethane (lOml). The mixture vas stirred at ambient temperature for 16 hours. The reaction mixture vas evaporated and dimethylformamide (lSml) was added to the residue. The mixture vas used vithout purification.

E~A~L~ 63 A = C02CH(He)et, B ~ OCH2CH20CH3 Purified by chromatography on silica gel (Varian Bond Elut S1 silica gel) using a 0 to lOX gradient of methanol in dichloromethane to give on oil; NHR(CDC13): 0.91(3H,t), 1.30(3H,d), 1.4-1.8(2H,m), 1.92(1H,m), 2.67(2H,t), 2.83(1H,d), 3.10(1H,d), 3.68(2H,m), 4.15(2H,m), 4.95(1H,m), 7.15(1H d of d), 7.18(1H,d), 7.43(1H,d); m/z 4102 (H~H).
The compound of formula 2 (Z z trifluoromethylsulphonoxy) used as starting material vas prepared in a similar manner to that described in Example 64 but sec-butanol vas used in place of ethanol.
The compound of formula 2 vas obtained as an oil; NHR: 0.90(3H,t), 1.30(3H,d), 1.70(2H,m), 3.3(3H,s), 3.67(2H,m), 4.2(2H,m), 5.02(1H,m), 7.35(1H d of d), 7.48(2H,m); m/z 400(H) via the corresponding phenol;
NHR: 0.92(3H,t), 1.32(3H,d), 1.7(2H,m), 3.62(2H,m), 4.05(2H,m), 5.05(1H,m), 6.92(1H,d), 7.2(1H d of d), 7.28(1H,d), 10.2(1H,s); m/z 268(~).

e2AnPL~ 64 A = C02~t, B = OCH2CH2OCH3 Purified by trituration vith acetonitrile and diethyl ether to give a solid, m.p. 153.5 - 154.5C; NHR(CDCl3): 1.38(3H,t), 1.64(1H,m), 1.5-1.4(1H,m), 1.8-1.95(1H, broad) 2.08(3H,m), 2.65(4H,m), 3.33(1H,d), 3.04(1H,d), 3.45(3H,s), 3.75(2H,m), 4.15(2H,m), 4.35(2H,q), 7.0(1H, d of d) and 7.42(2H,m).
The compound of formula 2 (Z = trifluoromethylsulphonyloxy) was prepared as follovs.
Sodium chlorite (8.08g) was added over a period of 30 seconds to a stirred solution W O 94/~ S ~ PCT/GB94/00910 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (see Example 41) and sodium methoxide in methanol (25Z by weight solution, 9.68ml) in dimethylsulphoxide (350ml) at 15C. After warming to room temperature and stlrring for 3 hours the mixture was added to water (600mls), acidified vith 2h aqueous hydrochloric acid, and extracted Yith dlethyl ether (4 x 250mls). The ethereal extracts were combined, washed ~ith Yater (2 x lOOml), dried (hgS04) and evaporated. The residue ~as crystallised from toluene to give 2-hydroxy-5-(2-methoxyethoxy)benzoic acid (4.1g) as solid m.p.
115-116C; NnR 3.3(3H,s), 3.65(2H,m), 4.05(2H,m), 6.9(1H,d), 7.15(1H, d of d), 7.25(1H,d); m/z 213(N+H).
Concentrated sulphuric acid (0.5ml) was added to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzoic acid (2g) ln ethanol (50ml). The mixture vas heated at reflux for 12 hours. The reactlon mlxture was added to sodlum hydrogen carbonate solutlon (5X by velght ln water, 200ml) and the aqueous mlxture was extracted with ethyl acetate (4 x 50ml). The organic extracts were combined, washed ~ith vater (50ml), brine, (50ml), dried (HgS04) and evaporated to give 2-ethoxycarbonyl-4-(2-methoxyethoxy)phenol (1.85g) as an oil; N~R:
1.35(3H,t), 3.31(3H,s), 3.6(2H,m), 4.0(2H,m), 4.3(2H,q), 6.9(1H,d), 7.18(1H d of d), 7.2(1H,d); m/z 241(nH). This was converted lnto the trlfluoromethane sulphonate ester using an analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxy)propionate. There vas thus obtained after chromatography on silica gel (Varian bond elut Sl sillca gel) uslng a gradient of 5 to 25Z ethyl acetate in hexane as eluent as an oil; NMR(6): 1.3(3H,t), 3.3(3H,s), 3.62(2H,m), 4.2(2H,m), 4.34(2H,q), 7.35(1H, d of d), 7.49(2H,m); m/z 373(H+H).

~AXPLE 65 Using the procedure described in Example 1 but using (-)-3-ethynyl-3-hydroxyquinuclidine in place of 3-ethynyl-3-hydroxyquinuclidine there was obtained (-)-3-l2-(2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyllquinuclidin-3-ol as an oil.

WO 94l254~9 ~ 7 ~ 5 PCT/GB94100910 The (-)-3-ethynyl-3-hydroxyquinuclidine used as starting material vas prepared as follovs.
A solution of (+)-3-ethynyl-3-butyryloxy quinuclidine (4.42g) in deionised vater (700ml) containing methanol (35ml) vas ad~usted to pH 7.0 using O.lh aqueous sodium hydroxide solutlon (dispensed by a pH autotitrator). A suspension of pig liver esterase (3.0ml, 3450 units, in 3.2n aqueous ammonium sulphate solution at pH8;
Sigma Chemical Company Ltd) vas added to the reaction mixture and the mlxture stirred at ambient temperature for 46 hours vhilst maintain~ng the pH at 7.0 using 0.1~ aqueous sodium hyroxide solution (dispensed from a pH autotitrater). During this period 112.5ml of the sodium hydroxide solution vas consumed, indicating that the hydrolysis vas 56Z complete. The pH of the reaction mixture vas adjusted to 2.52 using 2H aqueous hydrochloric acid and the mixture stirred for 20 minutes. 2h aqueous sodium hydroxide solution was added to the mixture to give a pH of 7.01 and the mixture extracted vith diethyl ether (12 x 150ml). The diethyl ether extracts vere combined, dried (hgS04) and evaporated to give an oil (2.43g) containing (-)-3-ethynyl-3-butyryloxyquinuclidine and some butyric acid.
The above oil containing(-)-3-ethynyl-3-butyryloxyquinuclidine vas treated with a solution of potassium hydroxide (2.24g) in methanol (50ml). The mixture was stirred at ambient temperature for 2 hours. The mixture vas evaporated and deionised water (2ml) was added to the residue to give a solid. The solid vas collected by filtration, washed ~ith water (2 x 2ml) and dried under vacuum over phosporus pentoxide to give (-)-3-ethynyl-3-hydroxyquinuclidine (611mg) as a solid, m.p.
199-202C, lall9D = -S6.1 (C = 1.02, methanol).

~AnrL~ 66 Using the procedure described in Example 1 but using (+)-3-ethynyl-3-hydroxyquinuclidine in place of 3-ethynyl-3-hydroxyquinuclidine there was obtained (+)-3-[2-(2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyl]quinuclidin-3-ol as an oil, [1 5D = + 21.8 (C = 0.316, ethanol).

7 ~9 ~

The (+)-3-ethynyl-3-hydroxyquinuclidine was prepared as follows.
A solution of (+)-3-ethynyl-3-butyryloxyquinuclidine (4.42g) in deionised vater (700ml) containing methanol (35ml) was ad~usted to pH 7.0 using an 0.1n aqueous sodium hydroxide solution (dispensed by a pH autotitrater). A suspension of pig liver esterase (8.0ml, 9200 units,in 3.2H aqueous ammQnium sulphate solution at pH8; Sig~a Chemical Company Ltd) was added to the reaction mixture and the mixture was stirred at ambient temperature vhilst maint~n~ng the pH
at 7.0 using O.ln aqueous sodium hydroxide solution (dispensed by a pH
autotitrater). After 5.5 hours, 7.3ml of the sodium hydroxide solution had been consumed, indicating that the hydrolysis vas 35Z
complete. The pH of the reaction mixture vas adjusted to 2.5 using 2H
aqueous hydrochloric acid and the mixture vas stirred for 10 minutes.
2~ aqueous sodium hydroxide solution vas then added to the mixture to give a pH of 7.05 and the mixture extracted vith diethyl ether (3 x 200ml, folloved by 12 x 150ml). The aqueous phase was separated, and freeze dried over a period of 48 hours to give a solid vhich was dissolved in deionised water (30ml). The solution vas filtered and the filtrate vas basified to pH9 using 10.8n sodium hydroxide solution to give a solid. The solid vas collected by filtration to give (+)-3-ethynyl-3-hydroxyquinuclidine, (554mg), m.p. 204-207C, lal20D =
+54.5 (C ~ 0.99, methanol).
The (+)-3-ethynyl-3-butyryloxyquinuclidine used as starting material Yas prepared as follovs.
A solution of n-butyl lithium (lOOml of a 2n solution in pentane) vas added portion-vise over a period of 20 minutes to a stirred solution of ethynyltrimethylsilane (19.6g) in dry tetrahydrofuran (400ml) at -70C. The mixture was stirred for 1 hour at -70C. A solution of 3-quinuclidinone (2.4g) in dry tetrahydrofuran (lOOml) was then added and the mixture stirred for 1 hour at -70C. Hethanol (lml) was then added to the mixture and the mixture allowed to warm to ambient temperature. The solvents were removed by evaporation. ~ethanol (500ml) and potassium carbonate (40g) were added to the residue and the mixture was stirred for 1 hour. The solvent was removed by evaporation. The residue was W 0 94/25459 ,~ 1 b ~ 5 PCT/GB94/00910 triturated vith water (500ml) and then dried in vacuo to give 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193-197C;
N~R(D~SO-d6): 1.5-1.3(1H,m), 1.4-1.6(1H,m), 1.7-1.95(3H,m), 2.55-2.8(5H,m), 2.95(1H,d), 3.3(1H,d) and 5.4(1H,s); m/z 152 (n+H).
A mixture of ( )-3-ethynyl-3-hydroxyquinuclidiDe (15.1g) and butyric anhydride (60ml) vas stirred at 120C for 5 hours. The reaction mixture vas cooled to ambient temperature, added to a saturated aqueous solution of sodium carbonate (11) and stirred for 3 hours. The mixture vas extracted vlth diethyl ether (3 x lOOml). The diethyl ether extracts were combined, vashed with saturated aqueous sodium carbonate solution, dried (HgS04) and evaporated to give (+)-3-ethynyl-3-butyryloxyquinuclidine as an oil, NnR(200nHz, DnSOd6):
0.90(3H,t), 1.40(1H,m), 1.57(4H,m), 1.85(1H,m), 2.28(3H,m), 2.66(4H,m), 3.03(1H,d), 3.18(1H,d) and 3.55(1H,s).

PLe 67 3-l2-l2-allyl-4-(2-ethoxycarbonylethyl)-phenyllethynyll-quinuclidin-3-ol (300mg) vas added to a stirred solution of sodium hydroxide pellets (150mg) in a mixture of ethanol (6ml) and water (3ml) at ambient temperature. After lS hours, the solution vas filtered and the filtrate vas evaporated. The residue vas stirred vith vater (5ml) and lH aqueous hydrochloric acid (6ml) vas then added. The mixture vas evaporated and the residue azeotroped vith toluene (2 x lOml). The residue vas treated vith dry acetone (lOml) and filtered. The insoluble residue vas vashed vith acetone (5ml).
The filtrate and vashings vere combined, evaporated and the residue triturated with ether. Evaporation of the ether gave 3-l2-l2-allyl-4-(2-carboxyethyl)-phenyllethynyllquinuclidin-3-ol hydrochloride salt as a solid (247mg), m.p. 41.4C (dec), NnR(ICD3]2SO/CD3COOD): 1.60-1.88(1H,m), 1.92-2.10(2H,m), 2.10-2.40(3H,m), 2.52(2H,t), 2.84(2H,t), 3.10-3.60(8H,m), 5.08(2H,m), 5.98(1H,m), 7.12(2H,m) and 7.37(1H,d); m/z 340(n~H).

E~AXrL~ 68 Using the procedure described in Example 67 but using +)-3-12-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyllquinculidin-3-21~795 ol as starting material, there vas thus obtained (+)-3-~2-(2-allyl-4-(2-carboxyethyl)phenyl)ethynyl)quinuclidine-3-ol hydrochloride, as a solid, m.p. 161-163C, NnR(DHSOd6/CD3COOD):
1.60-1.88(1H,m), l.g2-2.10(2H,m), 2.10-2.40~3H,m), 2.52~2H,t), 2.84(2H,t), 3.10-3.60(8H,m), 5.08(2H,m), 5.98(1H,m), 7.12(2H,m) and 7.37(1H,d); m/z 340(H+H).

E~PLE 69 Using the procedure described in Example 67 but using (-)-3-12-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyllquinuclidin-3-ol as starting material, there was thus obtained (-)-3-[2-(2-allyl-4-(2-carboxyethyl)phenyl)ethynyl)quinuclidin-3-ol hydrochloride as a solid, 161-163C; N~R: 1.60-1.88(1H,m), 1.92-2.10(2H,m), 2.10-2.40(3H,m), 2.52(2H,t), 2.84(2H,t), 3.10-3.60(8H,m), 5.08(2H,m), 5.98(1H,m), 7.12(2H,m) and 7.37(1H,d), m/z 340(H+H).

E~AnPLE 70 Using the procedure described in Example 1 but using 4-(methoxycarbonylmethyl)iodobenzene as starting material in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate and 3-ethenyl-3-hydroxyquinuclidine in place of 3-ethynyl-3-hydroxyquinuclidine, there was obtained, after recrystallisation from ethyl acetate, 3-[2-(4-methoxycarbonylmethoxyphenyl)vinyllquinculdine-3-ol as a solid, m.p. 169-170C, NHR(CDC13): 1.32-2.20(6H,s quinuclidine + OH at 1.9), 2.7-3.15(6H,m), 3.8(3H, d), 4.65(2H,s), 6.3-6.5(2H,m), 6.84-7.38(4H,m).

E~XPLE 71 Using a similar procedure to that described in Example 21 but using 3-(4-12-methoxyethoxylphenoxymethyl)-3-hydroxyquinuclidine borane complex as starting material there was obtained 3-(4-l2-methoxyethoxylphenoxymethyl)quinuclidin-3-ol as a solid, m.p.
93-95C, N~R: 1.5-1.8(1H,m), 1.7-2.0(2H,m), 2.1-2.4(2H,m), WO 94/25459 21 ~ 0 7 3 5 PCT/GB94/00910 2.9-3.4(9H,m), 3.55-3.65(2H,m), 3.9-4.1(4H,m), 5.45-5.55(1H,s), 6.8-6.95(4H,s) and 10.0-10.6(1H,br).
The 3-(4-l2-methoxyethoxylphenoxymethyl)-3-hydroxy-qulnuclidine borane complex used as starting material was prepared as follows.
Solid potassium carbonate (0.42g) was added to a solution of 4-methoxyethoxyphenol (0.44g) and 3-methylenequinuclidine oxide borane complex (0.31g) in dry dimethylformamide (lml) under an atmosphere of argon. The mixture vas stirred for 6 hours at 75C. The mixture was poured into water (3ml) and extracted ~ith ethyl acetate (3 x 3ml).
The ethyl acetate extracts were combined, washed with water (4 x 2.5ml), dried (Na2S04) and evaporated. The residue was crystallised from ether to give 3-(4-l2-methoxyethoxylphenoxymethyl)-3-hydroxy-quinuclidine borane complex as a colourless solid (0.53g), m.p.
107-109C; NnR(CDC13): 0.5-2.5(3H,br), 1.5-1.7(1H,m), 1.75-1.9(2H,m), 2.2-2.4(2H,m), 2.7-2.75(1H,s), 2.8-3.25(6H,m), 3.4-3.5(3H,s), 3.7-3.8(2H,m), 3.8-4.0(2H,q), 4.05-4.15(2H,m), 6.8-6.95(4H,m).

~A~rL~ 72 Using a similar procedure to that described in Example 21 but using 3-(4-ethoxycarboxyethylphenoxymethyl)-3-hydroxyquinuclidine borane complex as starting material there was obtained 3-(4-ethoxycarboxyethylphenoxymethyl)quinuclidine-3-ol as a solid m.p.
75-77C, NnR(DhSOd6): 1.2-1.3(3H,t), 1.3-1.45(1H,m), 1.5-1.65(2H,m), 2.05-2.2(2H,m), 2.3-2.65(1H,br), 2.5-3.1(10H,m), 3.8-4.05(2H,q), 4.05-4.2(2H,q), 6.8-6.9(2H,d), 7.1-7.2(2H,d).
The 3-(4-12-ethoxycarboxyethyllphenoxymethyl)-3-hydroxy-quinuclidine borane used as starting material was prepared from 4-ethoxycarbonyl ethyl phenol using an analogous procedure to that described in Example 71 for the preparation of the borane starting material.
The procedure described in Example 71 was repeated using 4-ethoxycarbonylethylphenol (0.47g) instead of 4-methoxyethoxyphenol.
There was thus obtained 3-(4-12-ethoxycarbonylethyl]phenoxymethyl-3-hydroxyquinuclidine borane complex as a yellow oil (0.74g).

21~7~
W O 94l25459 PCT/GB94/00910 ~AnPLE 73 Using a similar procedure to that described in Example 21, but using 3-(2-allyl-4-12-ethoxycarbonylethyllphenoxymethyl)-3-hydroxy quinuclidine borane complex as starting material there ~as obtained 3-(2-allyl-4-12-ethoxycarbonylethyllphenoxymethyl)quinclidine-3-ol as a solid, m.p. 160-162C~ N~R(D~SOd6/CD3COOD): 1.0-1.15(3H,t), 1.55-1.75(1H,m), 2.1-2.35(2H,m), 2.6-2.8(2H,t), 3.0-3.4(8H,m), 3.85-4.1(4H,m), 4.9-5.05(2H,m), 5.8-6.0(1H,m), 6.6(1H,s), 6.75-6.85(lH,d), 6.9-7.0(2H,m).
The 3-(2-allyl-4-12-ethoxycarbonylethyllphenoxymethyl)-3-hydroxyquinuclidine borane complex used as starting material vas prepared from 2-allyl-4-ethoxycarbonylethylphenol (0.5g) using a procedure analogous to that described in Example 74 for the preparation of the borane starting material. There was thus obtained 3-(2-allyl-4-12-ethoxycarbonylethyllphenoxymethyl)-3-hydoxyql-inuclidin e borane complex as an oil (0.87g); NnR(CDC13): 0.5-2.5(3H,br), 1.15-1.3(3H,t), 1.5-1.7(1H,m), 1.7-1.9(2H,m), 2.2-2.4(2H,m), 2.5-2.65(2H,t), 2.7-2.8(1H,s), 2.8-3.3(8H,m), 3.3-3.4(2H,d), 3.8-4.05(2H,q), 4.05-4.2(2H,q), 4.9-5.1(2H,m), 5.85-6.1(1H,m), 6.7-6.8(1H,d) and 6.9-7.1(2H,m).

~AnPL~ 74 Using a similar procedure to that described in Example 21 but using 3-(2-allyl-4-12-methoxyethoxylphenoxymethyl)-3-hydroxy-quinuclidine borane complex as starting material, there ~as obtained 3-(2-allyl-4-12-methoxyethoxylphenoxymethyl)quinuclidine-3-ol is a solid, m.p. 58-60C, NnR: 1.3-1.45(1H,m), 1.55-1.7(2H,m), 2.05-2.2(2H,m), 2.45-2.65(1H,br), 2.6-3.1(6H,m), 3.3-3.4(2H,m), 3.45(3H,s), 3.7-3.75(2H,m), 3.75-4.05(2H,q), 4.05-4.1(2H,m), 4.95-5.1(2H,m), 5.85-6.05(1H,m), 6.7-6.8(3H,m).
The 3-(2-allyl-4-12-methoxyethoxylphenoxymethyl)-3-hydroxy-quinuclidine borane used as starting material ~as prepared from 2-allyl-4-methoxyethoxyphenol (0.42g) using a method analogous to that described for the preparation of the borane starting material in Example 71.

W O 94/25459 ~ 1 fi ~ 7 ~ ~ PCT/GB94/00910 _ 95 _ There vas thus obtained 3-(2-allyl-4-12-methoxyethoxyl-phenoxymethyl)-3-hydroxyquinuclidine borane complex as an oil (0.48g).
N~R(CDC13): 0.7-2.4(3H,br), 1.6-1.7(1H,m), 1.7-1.85(2H,m), 2.2-2.4(2H,m), 2.75(1H,s), 2.8-3.25(6H,m), 3.3-3.4(2H,d), 3.45(3H,s), 3.7-3.75(2H,m), 3.8-4.0(2H,q), 4.05-4.1(2H,m), 4.9-5.1(2H,m), 5.85-6.0(lH,m) and 6.7-6.8(3H,m).

e~AXrL~ 75 The procedure described in Example 7 was repeated using 4-bromo-2-methoxyphenol in place of 4-iodophenol. There was thus obtained, after purification by flash chromatography on silica gel using a gradient of 0 to 20X methanol in dichloromethane cont~ini~g lX
a~monia (density, 0.88g/cm3) followed by recrystallisatlon from acetonitrile, 3-12-(3-methoxy-4-(2-methoxyethoxy)phenyl)ethynyl]-quinuclidin-3-ol as a solid, m.p. 130-131C, NhR: 1.21-1.40(1H,m), 1.47-1.65(1H,m), 1.77-2.00(3H,m), 2.66(4H,t), 2.75-3.12(2H,q), 3.60-3.70(2H,m), 3.76(3H,s), 4.02-4.12(2H,m), 5.49(1H,s) and 6.87-6.98(3H,m).

e~nPLe 76 The procedure described in Example 7 was repeated uslng 4-bromo-2-fluorophenol in place of 4-iodophenol. There was thus obtained 3-[2-(3-fluoro-4-(2-methoxyethoxy)phenyl)-ethynyllquinuclidin-3-ol as a solid, m.p. 136-139C, NhR:
1.21-1.43(lH,m), 1.49-1.70(lH,m), 1.75-2.00(3H,m), 2.70(4H,t), 2.75-3.15(2H,q), 3.30(3H,s), 3.60-3.75(2H,m), 4.14-4.26(2H,m), 5.62(1H,s) and 7.10-7.32(3H,m).

e~AnrLe 77 The procedure described in Example 1 was repeated using methyl-3-[3,5-diallyl-4-trifluoromethylsulphonyloxy)phenyl)propionate as starting material in place of ethyl 3-(3-allyl-4-trifluoromethyl-sulphonyloxy)phenyl)propionate. There was thus obtained, after purification by flash chromatography on silica gel using lOZ methanol in dichloromethane containing lZ ammonia (density, 0.88g/cm3) as eluent, 3-l2-(2~6-diallyl-4-(2-~ethoxycarbonylethyl)phenyl)ethynyl 21607~
W O 94l25459 quinuclidin-3-ol. Treatment vith fumaric acid gave, a solid vhich vas recrystallised from a mixture of acetone and diethyl ether to give the hemi-fumarate salt as a solid, 140-143C, NnR: 1.35-1.52(1H,m), 1.6-1.78(1H,m), 1.85-2.1(3H,m), 2.6(2H,m), 2.6(6H,t), 3.0(1H,br), 3.2(1H,br), 3.5(4H,d), 3.6(3H,s), 4.25(2H,br + H20), 5.08(4H,m), 5.85-6.05(2H,m), 6.52(1H,s) and 6.97(2H,s).
The methyl-3-l3,5-diallyl-4-(trifluoromethylsulphonyloxy)-phenyllpropionate used as starting material was prepared as follovs.
A mixture of methyl-3(3-allyl-4-hydroxyphenyl)propionate (12.3g), anhydrous potassium carbonate (13.8g), and allylbromide (8.64mls) in acetone (300ml) vas stirred at ambient temperature for tYo days. The reaction mixture vas filtered and the residue washed vith acetone. The filtrate and vashings were combined and evaporated to give methyl-3-(3-allyl-4-allyloxyphenyl)proprionate as a pale yellov oil (14.0g); NMR: 2.58(2H,t), 2.75(2H,t), 3.31(2H,d), 3.55(3H,s), 4.52(2H,d), 4.95-5.45(4H,m), 5.85-6.11(2H,m), 6.85(1H,d) and 7.0(2H,m).
Hethyl-3-(3-allyl-4-allyloxyphenyl)propionate (4g) vas heated at 250C for 10 minutes and then cooled. The residue was purified by flash column chromatography on silica gel uslng 50X ethyl acetate in n-pentane as eluent to give methyl-3-(3,5-dlallyl-4-hydroxyphenyl)propionate (2.5g); NnR:
2.5(2H,t), 2.7(2H,t), 3.32(4H,d), 3.57(3H,s), 4.96-5.1(4H,m), 5.82-6.05(2H,m), 6.75(2H,s) and 8.07(1H,s).
Trifluoromethane sulphonic anhydride (1.68g) vas added dropvise at 0-5C to a stirred solution of methyl-3(3,5-dially-4-hydroXyphenyl)propionate (2.5g) in dry pyridine (20ml). The mixture vas then stirred at ambient temperature for a further 16 hours. The pyridine vas removed by evaporation. The residue vas treated vith water (30ml) and the mixture vas extracted vith ether (3 x 30ml). The ethereal extracts were combined, washed vith vater (30ml), dried (HgS04) and evaporated. The residue vas purified by filtration through a short pad of silica gel (~erck Art 7736) using a mixture of 50X ether in n-pentane as eluent to give methyl-3-l3~5-diallyl-4-(trifluoromethylsulphonyloxy)phenyllpropionate W O 94t25459 ~ 1 ~ 0 ~ 9 v~ PCT/GB94/00910 (3.5g) as a pale yellov oil; NHR: 2.52(2H,t), 2.75(2H,t), 3.34(4H,d), 3.48(3H,s), 4.87-5.03(4H,m), 5.68-5.9(2H,m) and 7.03(2H,s).

~S~PL~ 78 Using the method described in Example 21, but using 2-hydroxymethyl-4-(2-methoxyethoxy)phenol as starting material and omitting the step of treating vith fumaric acid, there vas obtained 3-12-hydroxymethyl-4-(2-methoxyethoxy)phenyloxymethyllquinuclidin-3-ol as an oil (313ng) N~R(CDC13): 1.32-1.42(1H,br), 1.61(2H,br), 2.1(2H,br), 2.80(6h,v.br), 3.4(3H,s), 3.72(2H,m), 3.83(1H,d), 4.08(3H,m), 4.62(2H,q), 6.80(2H,d) and 6.90(1H,m); m/z 338(~+H).
The 2-hydroxymethyl-4-(2-methoxyethoxy)phenol used in above procedure vas prepared in the folloving manner.
Sodium borohydride (519mg) vas added to a solution of 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (5.55g) in ethanol (25ml) vhilst maint~ning the temperature at 5C. The resultlng mixture vas stirred at 25C for 30 minutes. The mixture was poured lnto vater (lOOml) and acidified to pH4 using glacial acetic acid. The mixture vas extracted vith ethyl acetate (3 x lOml). The ethyl acetate extracts vere combined, vashed vith brine (15ml), dried (HgS04) and evaporated to give an oil (4.1g). This oil vas purified by flash chromatography on silica gel (Herck Art No 3985) using a gradient of 30 to 55% ethyl acetate/hexane as eluent to give 2-hydroxymethyl-4-(2-methoxyethoxy)phenol as an oil (2.67g); NnR:
3.0(3H,s), 3.6(2H,m), 3.96(2H,m), 4.45(2H,d), 4.96(1H,t), 6.64(2H,m), 6.87(1H,d) and 8.84(1H,s); m/z 198(H).
The 2-hydroxy-5-(2-methoxyethoxy)bPn7~1dehyde used as starting material vas prepared as in example 41.

~A~rL~ 79 3-12-(2-formyl-4-(2-methoxycarbonylethyl)phenyllethynyll-quinuclidin-3-ol (575mg) vas stirred vith methanol (25ml) at ambient temperature under an atmosphere of argon. Sodium borohydride (329mg) vas added portionuise over 5 minutes to the reaction mixture and stirring continued at ambient temperature overnight. Uater (25ml) vas added and the mixture vas extracted vith ethyl acetate (25ml). The W O 94/25459 2 1 6 0 ~ ~ ~

organic phase vas separated, washed with saturated aqueous sodium carbonate (3 x 25ml), water (3 x 25ml), dried (HgS04) and evaporated.
The residue vas purified by elution through silica gel (lOg Bond elut column) with a gradient of 0-30X methanol in dichloromethane to give 3-[2-(2-hydroxymethyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl~-quinuclidin-3-ol (160mg) as a solid, m.p. 35.8C; microanalysis, found: C, 69.2; H, 7.5; N, 3.9X C20H25N04 0.2 H20 requires: C, 69.2;
H, 7.38; N, 4.04Z; NHR(CDC13): 1.4(1H,m), 1.66(1H,m), 2.02(3H,m), 2.62(2H,t), 2.8(3H,m), 2.95(2H,t), 3.03(1H,d)j 3.27(1H,d), 3.66(3H,s), 4.75(2H,s), 7.07(1H,m) and 7.3(2H,m); m/z 344 (H+H).

E~AXPLE 80 Using the method described in Example 1, but carrying out the reaction at ambient temperature overnight and with 2-iodophenylacetonitrile (667mg) in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thus obtained 2-[2-(2-cyanomethyl phenyl)ethynyllquinuclidin-3-ol as a solid (292mg), m.p. 147.1C, microanalysis found: C, 75.6; H, 7.1; N, 10.4Z C17H18N20 0.25 H20 requires: C, 75.4; H, 6.88; N, 10.3X; N~R:
1.3(1H,m), 1.59(1H,m), 1.94(3H,m), 2.69(4H,m), 2.84(1H,d), 3.17(1H,d), 4.05(2H,s), 5.63(1H,s) and 7.41(4H,m); m/z 267(H+H).

E~nrLE 81 Using the method described in Example 1 but carrying out the reaction at ambient temperature overnight and with methyl 3-(3-formyl-4-trifluoromethanesulphonyloxyphenyl)propionate (884mg) in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-propionate, there was thus obtained 3-l2-12-formyl-4-(2-methoxycarbonylethyl)phenyl)ethynyllquinuclidin-3-ol as a solid (437mg), m.p. 182.3C; microanalysis, found: C, 69.4; H, 6.8; N 4.0%
C20H23N04 0.25 H20 requires: C, 69.4; H, 6.85; N, 4.05X; NHR:
1.32(1H,m), 1.62(1H,m), 1.9(2H,m), 2.68(6H,m), 2.85(1H,d), 2.93(2H,t), 3.14(1H,d), 3.57(3H,s), 5.68(1H,s), 7.54(2H,m), 7.68(1H,m) and 10.39(lH,s); m/z 342(H+H).

WO 94/25459 21 6 ~ PCT/GB94/00910 _ 99 _ The methyl-3-(3-formyl-4-trifluoromethylsulphonyloxyphenyl)-propionate used as starting material ~as prepared in an analogous manner to the preparation of the starting material for Example 41.

~AnrLE 82 Sodiu~ borohydride (28.4mg) ~as added to a solution of 3-12-(3-formyl-4-(2-methoxyethoxy)phenyl)ethynyllquinuclidin-3-ol in methanol at 0C. The mixture ~as alloved to ~arm to amblent temperature and stirred for 1.5 hours. The reaction mixture vas poured onto vater (15ml) and the mixture extracted ~ith ethyl acetate (3 x 20ml). The ethyl acetate extracts ~ere combined, ~ashed ~ith brine solution (20ml), dried (ngS04) and evaporated. The residue ~as dissolved in acetonitrile (Sml) and diethylether ~as added to give, on cooling, a solid (262mg). This solid ~as further purified by crystallisation from acetonitrile to give 3-[2-(2-hydroxymethyl-4--(2-methoxyethoxy)phenyl)ethynyllquinuclidin-3-ol (217mg) as a solid, m.p. 98.5-100.0C; microanalysis, found C, 67.5X; H, 7.7X, N, 6.9Z, C1gH25N04 0.8CH3CN requires: C, 67.9X; H, 7.6X; N, 6.9Z; NnR(CDC13):
1.40(1H,m), 1.65(1H,m), 2.0(3H,s), 2.05(3H,m), 2.8(4H,t), 3.03(1H,d), 3.28(1H,d), 3.45(3H,s), 3.75(2H,t), 4.13(2H,t), 4.72(2H,s), 6.78(1H,m), 7.05(1H,d) and 7.3(1H,t); m/z 332(H+H).

E~AnrL~ 83 Using a similar procedure to that described in Example 1 but using (+)-3-ethynyl-3-hydroxyquinuclidine in place of 3-ethynyl-3-hydroxyquinuclidine and methyl 4-13-allyl-4-trifluoromethylsulphonyloxyphenyl)butanoate in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate, there ~as thus obtained (+)-3-[2-(2-allyl-4-(3-methoxycarbonylpropyl)-phenyl)ethynyllquinuclidin-3-ol as a gum, NHR(CDC13): 1.3-1.5(1H,m), 1.55-1.75(1H,m), 1.9-2.15(2H,m), 2.3-2.4(2H,t), 2.6-2.7(2H,t), 2.8-3.0(4H,m), 3.0-3.15(1H,d), 3.25-3.4(1H,d), 3.5-3.55(2H,m), 3.65(3H,s), 5.0-5.1(2H,d), 5.9-6.05(1H,m), 6.95-7.05(2H,d) and 7.3-7.4(1H,d); 5D = +24.1.
The methyl 4-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-butanoate used as starting material ~as prepared in a similar manner 2~0795 to ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (described in Example 1).

~AnPLL 84 Using the method described in Example 83 but uslng (-)-3-ethynyl-3-hydroxyquinuclidine in place of (+)-3-ethynyl-3-hydroxyquinuclidlne there vas thus obtalned (-)-3-[2-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyll-quinuclidine-3-ol; NHR(CDC13): 1.4-1.5(1H,m), 1.55-1.8(1H,m), 1.8-2.2(5H,m), 2.1-2.4(2H,t), 2.6-2.7(2H,t), 2.8-3.0(2H,m), 3.0-3.15(1H,d), 3.3-3.4(1H,d), 3.4-3.6(2H,m), 3.66(3H,s), 5.0-S.1(2H,m), 5.9-6.1(1H,m), 6.95-7.05(2H,m), 7.3-7.4(1H,d), a25D = -20 3O

e~A~L~ 85 Sodium hydroxide (44mg) was added to a mixture of (+)-3-12-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyll-quinuclidin-3-ol, ~ater (lml) and methanol (0.5ml). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture vas evaporated to dryness. ~ater was added to the residue, and the mixture acidified using dilute aqueous hydrochloric acid. The mixture was evaporated and acetone was added to the res1due. The mixture was filtered and the filtrate evaporated to give (+)-3-[2-(2-allyl-4-(3-carboxypropyl)phenyl)ethynyllquinuclidin-3-ol hydrochloride as a gum (62mg), NHR: 1.7-1.9(3H,m), 1.9-2.1(1H,m), 2.1-2.3(4H,m), 2.S-2.65(2H,m), 3.1-3.6(4H,m), 5.0-5.15(2H,d), 5.46(1H,m), 6.45(1H,t), 7.05-7.1(2H,m) and 7.3-7.4(1H,d); a25D = ~3 0 ~AXPLE 86 Using a similar method to that described in Example 1 but using (+)-3-ethynyl-3-hydroxyquinuclidine and methyl 5-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)pentanoate as starting materials there was thus obtained (+)-3-12-(2-allyl-5-(4-methoxycarbonylbutyl)phenyl)ethynyl]quinuclidine-3-ol, NHR:
1.3-1.5(1H,m), 1.55-1.7(5H,m), 1.7-2.2(4H,m), 2.25-2.40(2H,m), 2.55-2.7(2H,m), 2.7-3.0(4H,m), 3.0-3.1(1H,d), 3.25-3.4(1H,d), W O 94l25459 21 6 ~ 7 ~ ' PCT/GB94100910 3.4-3.5(2H,m), 3.65(3H,s), 5.0-5.1(2H,m), 5.85-6.1(lH,m), 6.9-7.0(2H,m) and 7.3-7.4(1H,d); a 5D = +19.2 E~A~PLE 87 A mixture of 3-[2-(2-allyl-4-methoxycarbonylphenyl)-ethynyl]quinuclidin-3-ol (0.64 g), sodium cyanide (50 mg) and N,N-dimethylethanolamine (10 ml) vas heated at 90C for 24 hours. The mixture was evaporated to give an oil which was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried (HgS04) and evaporated. The residue was purified by flash column chromatography on silica gel using lOZ methanol in dichloromethane containing lZ ammonia (density 0.88 g/cm3) as eluent to give 3-[2-(2-allyl-4-(2-(N,N-dimethylamino)ethoxycarbonyl)phenyl)-ethynyl~quinuclidin-3-ol as a gum (0.559 g); microanalysis found: C, 66.7; H, 7.6; N, 6.7Z, C23H30N203Ø4CH2C12Ø1 H20 requires, C, 67.2; H, 7.47; N, 6.7Z; NHR (CDC13): 1.32-1.55(1H, m), 1.55-1.88(1H, m), 1.88-2.20(3H, m), 2.33(6H, s), 2.70(2H, t), 2.65-3.15(4H, m), 3.07(1H, d), 3.33(1H, dd), 3.56(2H, d), 4.41(2H, t), 4.98-5.15(2H, m), 5.29(CH2C12), 5.85-6.10(1H, m), 7.43(1H, d) and 7.71-7.90(2H, m); m/Z 383 (~+H).

E~AnPLE 88 A methanolic solution of potassium hydroxide was added to a solution of 3-[2-(2-allyl-4-methoxycarbonylphenyl)ethynyll-quinuclidin-3-ol (0.975 g) in methanol (10 ml) until hydrolysis was complete as judged thin layer chromatography. The precipitate formed was collected by filtration, washed with pentane and dried over phosphorus pentoxide. A mixture of the dried solid (0.45 g) and 2-chloro-N,N'-dimethylacetamide (0.144 ml) in 5 ml of 1,3-dimethyl-3,4,6-tetrahydro 2-pyrimidinone (DHPU) was heated at 70C for 3 hours.
The mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic phase was washed with brine and dried (HgS04). Evaporation gave an oil which was purified by chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm3) as eluent to give 3-12-(2-allyl-4-(2-N,N'-dimethylacetamidoxy)carbonyl W O 94/25459 2 1 6 0 7 ~ ~ PcT/GBg4/ooglo phenyl)ethynyllquinuclidin-3-ol as a gum (56 mg); microanalysis found: C, 67.4; H, 7.5; N, 7.1X; C23H28N204 0.75H20 requires: C, 67.4; H, 7.25; N, 6.83X; NHR (CDC13): 1.35-1.55(1H, m), 1.55-1.80(1H, m), 1.87-2.20(3H, m), 2.75-3.15(11H, m), 3.33(1H, dd), 3.56(2H, d), 4.94(2H, s), 4.98-5.15(2H, m), 5.85-6.0~(1H, m), 7.45(1H, d) and 7.80-8.00(2H, m); m/Z 397 (H+H).

~SA~PL~ 89 A mlxture of 3-l2-(2-ethoxy-4-formylphenyl)ethynyllquinuclidin-3-ol (598 mg), carbethoxymethylenetriphenylphosphorane (1.04 g) in toluene (lO ml) was heated at 100C for S hours. The reaction mixture vas cooled to ambient temperature and the toluene evaporated to give a solid vhich was crystallised from acetonitrile to give 3-l2-(2-ethoxy-4-(2-ethoxycarbonylethenyl)phenyl)ethynyllquinuclidin-3-ol (328 mg) as a solid, m.p. 152-153C; microanalysis found: C, 71.5;
H, 7-3; N, 3.7Z; C22H27N04 requires: C, 71.5: H, 7.37; N, 3.79Z; NHR
(CDCl3): 1.33(3H, t), 1.36-l.S2(4H, m), 1.55-1.70(1H, m), 1.90-2.30(4H, m), 2.73-3.00(4H, m), 3.04(1H, d), 3.34(1H, dd), 4.09(2H, q), 4.26(2H, q), 6.33-6.45(1H, d), 6.93-7.03(1H, d,), 7.03(1H, dd), 7.35(1H, d), 7.60(lH, d); m/Z 370 (H+H).
The 3-12-(2-ethoxy-4-formylphenyl)ethynyllquin~lclidine-3-ol used as starting material was prepared as follovs.
Ethyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate vas prepared from ethyl vanillin using the procedure described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethyl-sulphonyloxyphenyl)propionate. Thus there vas obtained 3-ethoxy-4-trifluoromethylsulphonyloxybenzaldehyde as an oil; N~R
(CDC13): 1.50(3H, t), 4.22(2H, q), 7.36-7.58(3H, m), 9.97(1H, s); m/Z 299 (H+H).
Using the method described in Example 1 but vith 3-ethoxy-4-trifluoromethylsulphonyloxybenzaldehyde in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thus obtained 3-l2-{2-ethoxy-4-formylphenyl}ethynyllquinuclidin-3-ol as a solid, m.p. 148-153C; microanalysis, found: C, 71.8; H, 7.3; N, 4.SX;
C18H21N03 requires: C, 72.2; H, 7.07; N, 4.68X; NHR (CDC13):
1.35-1.54(1H, m), 1.45(3H, t), 1.56-1.73(1H, m), 1.98-2.20(3H, m), WO 94/254~9 ,~16 0 7 ~ ~ PCT/GB94/00910 2.85(4H, br t), 3.05(1H, d), 3.37(1H, dd), 4.13(2H, q), 7.30-7.40(2H, m), 7.50(1H, d), 9.93(1H, s); m/Z 300 (~+H).

~AXPLE 90 The procedure described in Example 35 ~as repeated using (+)-3-ethynyl-3-hydroxyquinuclidine in place of (+)-3-ethynyl-3-hydroxy quinuclidine to give (+)-3-l2-(2-allyl-4-(3-methoxypropyl)-phenyl)ethynyllqulnuclidin-3-ol as an oil, NHR: 1.3-1.5 (lH, m), 1.6-1.8 (3H, m), 1.8-2.2 (3H, m), 2.53-2.65 (2H, t), 2.65-3.15 (6H, m), 3.2 (3H, s), 3.25-3.35 (2H, t), 3.5-3.6 (2H, d), 5.0-5.1 (2H, m), 5.6 (lH, s), 5.8-6.6 (lH, m), 7.0-7.1 (2H, d) and 7.2-7.3 (2H, d).
[l2D+15.4.

~L~ 91 The procedure described in Example 35 vas repeated using (-) 3-ethynyl-3-hydroxyquinuclidine in place of (~) 3-ethynyl-3-hydroxyquinuclindine to give (-)-3-12-(2-allyl-4-(3-methoxypropyl)phenyl)ethynyll- quinuclindin-3-ol as an oil, NHR: 1.3-1.5 (lH, m), 1.5-1.7 (lH, m), 1.7-1.85 (2H, m), 1.85-2.05 (3H, m), 2.55-2.65 (2H, t), 2.65-2.8 (4H, m), 2.8-3.0 (lH, d), 3.05-3.15 (lH, d), 3.2 (3H, s), 3.25-3.35 (2H, t), 3.4-3.5 (2H, d), 5.0-5.1 (2H, m), 5.6 (lH, s), 5.9-6.0 (lH, m), 7.0-7.1 (2H, d) and 7.2-7.3 (2H, d); Il20D -19.4.

ESAnPL~ 92 Using the procedure described in Example 11, but ~ith l-allyl-2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxymethyl)benzene in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there ~as thus obtained 3-12-(2-allyl-4-(2-methoxyethoxymethyl)phenyl)ethynyl]-quinuclidin-3-ol as an oil, NHR: 1.25-1.45 (lH, m), 1.5-1.7 (lH, m), 1.8-2.1 (3H, m), 2.6-3.2 (6H, m), 3.3 (3H, s), 3.45-3.6 (6H, m), 4.5 (2H, s), 5.0-5.2 (2H, m), 5.6 (lH, s), 5.9-6.1 (lH, m) and 7.1-7.4 (3H, m).
The compound of formula 2(2 = trifluoromethysulphonyloxy) used as starting material was prepared as follows.
2-(4-bromobenzyloxy) l-methoxyethane (preparation described in Example 11) (10 g) was added to a stirred mixture of oven dried magnesium WO 94/25459 21~ 0 ~ ~ ~ PCT/GB94/00910 (2.74 g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A
crystal of iodine vas added and the mixture heated until an exothermic reaction com~enced. A solution of the remaining 2-(4-bromo-benzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml) was added dropwise to maintaln the temperature of the reaction mixture at reflux.
Vhen the addition was complete the mixture was heated at reflux for a further 20 minutes, allowed to cool and added to trimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10C, dropwlse over 45 minutes whilst maintaining the temperature belov -5C. After stirring for 15 minutes, chilled acetic acid (9.36 g) was added, followed by the dropvise addition of 30Z hydrogen peroxide (11.77 ml) in vater (11 ml) whilst maintaining the temperature belov 0C. The mixture ~as allowed to warm to ambient te~perature over a period of 20 minutes and then washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown. The organic layer was dried (HgS04) and evaporated. The residue vas dissolved in ether (100 ml) and extracted into IH aqueous sodium hydroxide (50 ml x 3). The a~ueous extract was acidified with 2H aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (3 x 50 ml). The ethyl acetate extracts vere combined, dried (HgS04) and evaporated. The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as a colourless oil;
NnR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s), 6.7-6.8 (2H, d), 7.1-7.3 (2H, d).
This material was used to prepare using an analogous procedure to that described in example 35 for the preparation of 3-(-4-allyloxyphenyl)propanol. There was thus obtained 2-(4-allyloxybenzyloxy)-1-methoxyethane as an oil. NhR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5-4.6 (4H, m), 5.2-5.5 (2H, m), 6.0-6.2 (lH, m), 6.8-6.9 (2H, d), 7.2-7.3 (2H, d).
This material was used to prepare 2-(2-allyl-4-hydroxybenzyloxy)-1-methoxyethane using an analogous procedure to that described in example 35 for the preparation of 3-(2-allyl-4-hydroxyphenyl)-1-methoxypropane. There was thus obtained 2-(2-allyl-4-hydroxybenzyloxy)-1-methoxy ethane as a colourless oil, NHR

W O 94/25459 21~ O ~ PCT/GB94/00910 (CDC13): 3.4 (SH, m), 3.5-3.7 (4H, m), 4.5(2H,s), 5.05-5.2 (3H, m), 5.9-6.1 (lH, m), 6.7-6.8 (lH, d), 7.05-7.15 (2H, m).
This material vas used to prepare 2-(3-allyl-4-trifluoromethylsulphonyloxybenzyloxy)-1-methoxyethane using an analogous procedure to that described in example 1 for the preparation of ethyl 3-(3-allyl-4- trifluoromethylsulphonyloxyphenyl)propionate.
There vas thus obtained 2-(2-allyl-4-hydroxybenzyloxy)-1-methoxyethane as a colourless oil, NHR (CDC13) 3.4 (3H, s), 3.45-3.55 (2H, d), 3.55-3.7 (4H, m), 4.6 (2H, s), 5.0-5.2 (2H, m), 5.8-6.0 (lH, m), 7.2-7.4 (3H, m).

E~HPLE 93 A solution of hydrogen chloride in ethanol vas added dropvise to a stirred solution of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol borane complex (0.3 g) in acetone (3 ml, analar) until the solution vas pHl. A solid separated and the mixture was stirred for 2 hours at ambient temperature under an atmosphere of argon. The solid vas collected by filtration and washed vith acetone (3 ml) to give 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol hydrochloride (0.27 g) as a yellov solid, m.p. 185-188C; microanalysis, found: C, 61.7; H, 7.1; N, 8.7X; C16H20N202 HCl 0.15 H20 requires: C, 61.7; H, 6.9; N, 9.0X; NHR:
1.55-2.05 (3H, m), 2.1-2.35 (2H, m), 2.95-3.5 (6H, m), 3.9-3.95 (2H, s), 4.0-4.15 (2H, q), 5.45-5.7 (lH, s), 6.95-7.05 (2H, d), 7.25-7.35 (2H, d) and 10.5-10.8 (lH, br), m/z 273 (H+H).
The 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol borane complex used as starting material vas prepared as follovs.
A mixture of 4-hydroxybenzyl cyanide (0.27 g), 3-methylenequinuclidine oxide borane complex (0.31 g), and anhydrous potassium carbonate (0.42 g) in dry dimethylformamide (1 ml) vas heated at 75C for 7 hours under an atmosphere of argon. There vas thus obtained 3-(4-cyanomethylphenyloxymethyl)quinuclidin-3-ol borane complex as an orange solid.

~AnPLE 94 The procedure described in Example 93 vas repeated using 3-(4-styrylphenoxymethyl)quinuclidin-3-ol borane complex (0.25 g), instead of 3-(4-cyanomethylphenoxy~ethyl)quinuclidin-3-ol borane complex, 2 1 ~ 3 ~

in acetone (5 ml, analar). There vas thus obtained 3-(4-styrylphenoxymethyl)quinuclidin-3-ol hydrochloride (0.23 g) as a colourless solid, m.p. 235-238C; microanalysis, found: C, 70.2; H, 7.1;
N, 3.6X; C22H25N02 HCl 0.25 H20 requires: C, 70.2; H, 7.1; N, 3.7X; NHR:
1.55-2.05 (3H, m), 2.1-2.35 (2H, m), 2.95-3.5 (6H, m), 4.0-4.2 (2H, q), 5.3-5.85 (lH, br), 6.9-7.1 (2H, d), 7.1-7.2 (2H, d), 7.2-7.3 (lH, m), 7.3-7.45 (2H, t) and 7.45-7.7 (4H, m), m/z 336 (H+H).
The 3-(4-styrylphenoxymethyl)quinuclidin-3-ol borane complex used as starting material vas prepared from 4-hydroxystilbene using an analagous procedure to that described in Example 93 for the preparation of the borane starting material. The procedure described in Example 93 vas repeated using 4-hydroxystilbene (0.39 g) instead of 4-hydroxybenzyl cyanide, except that the reaction mixture vas extracted vith ethyl acetate (50 ml). The ethyl acetate extract was vashed vith vater (3 x 20 ml), dried (Na2S04) and evaporated. There vas thus obtained 3-(4-styrylphenoxymethyl)quinuclidin-3-ol borane complex (0.28 g), as an off-vhite solid.

E~AnPLE 95 The procedure described in Example 93 vas repeated using 3-[4-(2-cyanoethyl)phenoxymethyllquinuclidin-3-ol borane complex (0.3 g), instead of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol borane complex, except that the reaction mixture vas evaporated. The residual gum vas dissolved in aqueous lH aqueous hydrochloric acid (3 ml) and the solution vas vashed vith ethyl acetate (4 x 3 ml). The aqueous layer vas basified vith solid sodium carbonate and the mixture vas extracted vith ethyl acetate (3 x 4 ml). The ethyl acetate extracts vere combined, dried (Na2S04) and evaporated. The solid residue ~as triturated vith diethyl ether to give 3-l4-(2-cyanoethyl)phenoxymethyllquinuclidin-3-ol (0.15 g) as a colourless solid, m.p. 92-94C; microanalysis, found: C, 70.0; H, 7.8; N, 9.5Z; C17H22N202 0.3H20 requires: C, 70.0; H, 7.8; N, 9.6X; NnR
(CDCl3): 1.3-1.5 (lH, m), 1.5-1.7 (2H, m), 2.0-2.2 (2H, m), 2.3-2.6 (lH, br), 2.55-2.65 (2H, t), 2.6-3.1 (8H, m), 3.8-4.1 (2H, q), 6.85-6.95 (2H, d) and 7.1-7.2 (2H, d), m/z 287 (H+H).
The 3-~4-(2-cyanoethyl)phenoxymethyllquinuclidin-3-ol borane complex used as starting material ~as prepared from W O 94/25459 ~ 1 ~ 0 7 ~ ~ PCT/GB94/00910 3-(4-hydroxyphenyl)propionitrile using an analogous procedure to that described in Example 93 for the preparation of the borane starting material. The procedure described in Example 93 ~as repeated using 3-(4-hydroxyphenyl)propionitrile (0.29 g) instead of 4-hydroxybenzyl cyanide. There ~as thus obtained 3-[4-(2-cyanoethyl)phenoxymethyll-quinuclidin-3-ol borane complex (0.32 g) as an oil.

~SA~PLE 96 In a similar manner to that in Example 93, 3-(2-allyl-4-hydroxymethylphenyloxymethyl)quinuclidin-3-ol borane complex (157 mg) was deprotected to give 3-(2-allyl-4-hydroxymethylphenyloxymethyl)-quinuclidin-3-ol hydrochloride (121 mg) vhich ~as obtained as a ~hite crystalline solid hydrochloride directly from the reaction mixture on adding an equal volume of ether; microanalysis, found: C, 62.2; H, 7.7;
N, 3.8Z; C18H25N03 hydrochloride hemihydrate requires, C, 62.0; H, 7.8;
N, 4.01Z; NHR: 1.6-2.0 (3H, m), 2.3-2.4 (2H, bs), 2.9-3.7 (9H, m), 3.9-4.2 (2H, q), 4.4 (2H, s), 4.95-5.15 (2H, m), 5.15-5.65 (lH, bs), 5.85-6.1 (lH, m) and 6.85-7.2 (3H, m), m/z 304 (n+H).
The starting material ~as prepared as follo~s. In a manner similar to example 51 but using a 15 hour reaction time, 2-allyl-4-formylphenol (1.0 g) ~as reacted ~ith 3-methylenequinuclidine oxide (0.944 g) in DhF (3.1 ml) to afford 3-(2-allyl-4-formylphenyloxy-methyl)quinuclidin-3-ol borane complex (869 mg), obtained as a vhite crystalline solid after purification by chromatography on silica gel eluted with 15Z acetone/pentane, NhR: 0.8-2.0 (6H, m), 2.0-2.3 (2H, bs), 2.65-3.1 (6H, m), 3.44-3.49 (2H, d), 4.14 (2H, s), 5.0-5.35 (3H, m), 5.87-6.11 (lH, m), 7.18-7.22 (lH, d), 7.68-7.69 (lH, d), 7.75-7.87 (lH, dd) and 9.86 (lH, s).
A solution of 3-(2-allyl-4-formylphenyloxymethyl-3-hydroxy-quinuclidine borane complex (175 mg) in gently ~armed ethanol (2.0 ml) was treated uith sodium borohydride (24 mg). After 1 hour the ethanol vas removed by evaporation and the residue partitioned bet~een ether (3 x 5 ml) and ~ater (2 ml). The ether layers were combined ~ashed Yith water (3 ml), dried (HgS04) and evaporated to give a colourless gum (176 mg) ~hich ~as purified by chromatography on silica gel eluted successively ~ith 20% and then 30% acetone/pentane to afford W 0 94/25459 216 0 71~ ~ PCT/GB94/00910 3-(2-allyl-4-hydroxymethylphenyloxymethyl)quinuclidin-3-ol borane complex (169 mg) as a colourless gum.

~S~nPL~ 97 Sodiu~ borohydride (380 mg) was added to a solutlon of 3-[2-(2-allyl-4-formylphenyl)ethynyllquinuclidin-3-ol (2.95 g) in ethanol (50 ml) ~hilst maintaining the temperature at 5C. The resultin~ mixture was stirred at 25C for 2 hours and the ethanol was then evaporated. The residue ~as stirred with acetone (25 ml) and lH aqueous hydrochloric acid (50 ml) was then added. The resulting mixture was stirred at 25C for 1 hour and sodium hydrogen carbonate (4.5 g) ~as then added. The mixture vas extracted ~ith ethyl acetate (3 x 50 ml), the ethyl acetate extracts combined, ~ashed with brine (50 ml), dried (Na2S04) and evaporated. The residue ~as dissolved in dichloromethane (85 ml) and triethylamine (1.8 ml) ~as added. A solution of pivaloyl chloride (1.14 g) in dichloromethane (8 ml) was added to the mixture whilst maintaining the temperature at 5C. The resulting mixture vas stirred at 25C for 12 hours. The dichloromethane vas removed by evaporation and the residue vas dissolved in ethyl acetate (215 ml). The mixture ~as ~ashed with brine (100 ml), saturated sodium hydrogen carbonate solution (100 ml), dried (Na2S04) and evaporated to give a residue which vas purified by medium pressure column chromatography on alumina (Alumina N32-63) using a 49:1 (v/v) mixture of ethyl acetate and methanol as eluent to give 3-[2-(4- trimethylacetyloxymethyl-2-allylphenyl)ethynyl]quinuclidin-3-ol as a solid, m.p. 73C; microanalysis, found: C, 74.9; H, 8.2; N, 3.8X;
C24H31N03 0.2H20 requires: C, 74.9; H, 8.2; N, 3.6X; N~R (CDCl3): 1.2 (9H, s), 1.4 (lH, m), 1.65 (lH, m), 2.1 (3H, m), 2.3 (lH, m), 2.8 (4H, t), 3.1 (lH, d), 3.3 (lH, dd), 3.5 (2H, d), 5.1 (4H, m), 5.9 (lH, m), 7.1 (2H, m) and 7.4 (lH, d), m/z 382 (H+H).

~AnPLL 98 Sodium borohydride (380 mg) was added to a solution of 3-[2-(4-formyl-2-allylphenyl)ethynyllquinuclidine-3-ol (2.95 g) and methylamine hydrochloride (1.01 g) in ethanol (50 ml) whilst maintaining the temperature at 5C. The resulting mixture was stirred at 25C for 12 hours, filtered and the filtrate evaporated to leave a residue which was WO 94/25459 2 ~ 6 ~ 7 9 5 PCT/GB94/00910 suspended in lH aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3 x 50 ml). The ethyl acetate extracts were combined, washed with brine (50 ml), dried (Na2S04) and evaporated. The residue was triturated with diethyl ether to give 3-[2-(4-methylaminomethyl-2-allylphenyl)ethynyllquinuclidin-3-ol as a solid, m.p. 80C; microanalysis, found C, 75.1; H, 8.3; N, 8.6X;
C2oH26N20Ø5H20 requires: C, 75.2; H, 8.5; N, 8.8X; NHR (CDC13): 1.4 ( lH, m), 1.65 (lH, m), 2.1 (5H, m), 2.5 (3H, s), 2.8 (4H, t), 3.1 (lH, d), 3.3 (lH, dd), 3.5 (2H, d), 3.7 (2H, s), 5.1 (4H, m), 5.9 (lH, m), 7.1 (2H, m) and 7.4 (lH, d), m/z 311 (H+H).
The 3-12-(4-formyl-2-allylphenyl)ethynyl~quinuclidine-3-ol used as starting material was prepared using the method described in Example 1, but with 3-allyl-4-trifluoromethylsulphonyloxybenzaldehyde in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)- propionate. There vas thus obtained 3-12-(4-formyl-2-allylphenyl)-ethynyl]quinuclidine-3-ol as a solid, m.p. 132-133C; microanalysis, found: C, 76.5; H, 7.3; N, 4.5X ClgH21N02 0.2 H20 requires C, 76.4; H, 7.2; N, 4.7Z; NnR (CDC13): 1.4 (lH, m), 1.65 (lH, m), 2.1 (3H, m), 2.8 (4H, t), 3.1 (lH, d), 3.3 (lH, dd), 3.6 (2H, d), 5.1 (2H, m), 5.9 (lH, m), 7.3 (lH, d), 7.5 (2H, m) and 10.0 (lH, s), m/z 296 (~+H).
The 3-allyl-4-trifluoromethylsulphonyloxybenzaldehyde was prepared using the method described in Example 1, but with 4-hydroxybenzaldehyde in place of ethyl 3-(4-hydroxyphenyl)- propionate.
There was thus obtained 3-allyl-4-trifluoromethyl-sulphonyloxybenzaldehyde as an oil; NHR (CDC13): 3.6 (2H, d), 5.2 (2H, m), 6.0 (lH, m), 7.5 (lH, d), 7.9 (2H, m) and 10.0 (lH, s).

e~AnPL~ 99 3-12-(4-formyl-2-allylphenyl)ethynyllquinuclidin-3-ol (1.0 g) and methoxylamine hydrochloride were dissolved in ethanol (35 ml) and the mixture stirred at 25C for 12 hours. The ethanol was evaporated and the residue crystallised from ethyl acetate to give 3-12-(4-methoxyiminomethyl-2-allylphenyl)ethynyllquinuclidin-3-ol hydrochloride as a solid, m.p. 143C; microanalysis, found: C, 64.7; H, 7-0; N, 8-0X C20H24N202 HCl. 0.5H20 requires C, 64.9; H, 7.0; N, 7.6X;
NnR (lCD312SO/CD3COOD): 1-5-2-3 (5H, m), 3.2 (4H, t), 3.4 (lH, d), 3.6 W O 941254~9 2 1 6 0 7 ~, (lH, dd), 3.9 (3H, s), 5.1 (2H, m), 6.0 (lH, m), 7.5 (3H, m) and ~.2 (lH, s), m/z 325 (~+H).

E~AXrL~ 100 Bis (triphenylphosphine)-palladium (II) chloride (147 mg) and copper (I) iodide (74 mg) were added to a solution of dlethyl (3 allyl 4 trifluoromethylsulphonyloxybenzylidine)malonate (3.3 g) and 3-ethynylquinuclidine-3-ol (1.37 g) in dimethylformamide (17 ml) and triethylamine (1.47 ml) at 5C under an atmosphere of argon. The mixture was stirred at 25C for 12 hours. ~ater (255 ml) was added and the mixture extracted with ethyl acetate (3 x 100 ml). The ethyl acetate extracts were combined, washed vith brine (100 ml), dried (Na2S04) and evaporated to give a residue which vas purified by medium pressure column chromatography on alumina (Alumina N32-63) using a 99.1 (v/v) mixture of ethyl acetate and methanol as eluent to give 3-12-(4-(2-dicarbethoxyethylenyl)-2-allylphenyl)ethynyl]quinuclidin-3-ol as a solid, m.p. 112C, microanalysis, found: C, 71.1, H, 7.3; N, 3.1Z;
C26H31N05 requires C, 71.4; H, 7.1; N, 3.2Z; NnR (CDCl3): 1.3 (6H, t), 1.4 (lH, m), 1.65 (lH, m), 2.1 (3H, m), 2.8 (4H, t), 3.1 (lH, d), 3.3 (lH, dd), 3.5 (2H, d), 4.1 (4H, q), 5.1 (2H, m), 5.9 (lH, m), 7.1 (2H, m), 7.4 (lH, d) and 7.65 (lH, s), m/z 438 (N+H).
The diethyl (3-allyl-4-trifluoromethylsulphonyloxy-benzylidine)malonate used as starting material was obtained as folloYs.
3-Allyl-4-hydroxybenzaldehyde (2.0 g) and diethylmalonate (2.37 g) were dissolved in toluene (50 ml) and piperidine (4 drops) and acetic acid (12 drops) were added. The mixture was heated at reflux using a Dean ~ Stark water separator until no more water was collected (2 hours).
The toluene was evaporated to give a residue which vas dissolved in diethyl ether (50 ml), ~ashed Yith water (50 ml), saturated sodium hydrogen carbonate (25 ml), brine (25 ml), dried (ngS04) and evaporated to give a residue which was purified by medium pressure column chromatography on silica gel using a 4:1 (v/v) mixture of isohexane and ethyl acetate as eluent to give diethyl (3-allyl-4-hydroxybenzylidine)malonate as an oil, NnR (CDCl3) 1.3 (6H, t), 3.4 (2H, d), 4.3 (4H, q), 5.2 (2H, m), 6.0 (lH, m), 6.6 (lH, d), 7.2 (2H, m) and 7.6 (lH, s).

~ fiO7~

Trifluoromethyl sulphonic anhydride (2.12 ml) was added dropwise over 20 minutes to a stirred solution of diethyl (3-allyl-4-hydroxybenzylidine)malonate (3.7 g) in pyridine (12 ml) at 0C
under an atmosphere of argon. The mixture was stirred at 0C for 16 hours and was then added to cold water (180 ml). The aqueous mixture was extracted with diethyl ether (3 x 100 ml), the diethyl ether extracts combined, washed with lH aqueous hydrochloric acid (3 x 50 ml), brine (100 ml), dried (HgS04) and evaporated to give a residue which was purified by medium pressure column chromatography on silica gel using a 19:1 (v/v) mixture of isohexane and ethyl acetate as eluent to give diethyl (3-allyl-4-trifluoromethyl-sulphonyloxybenzylidine)malonate as an oil NHR (CDC13): 1.3 (6H, t), 3.5 (2H, d), 4.3 (4H, q), 5.2 (2H, m), 6.0 (lH, m), 7.3 (2H, m), 7.4 (lH, s) and 7.7 (lH, s).

~PL~ 101 A mixture of 3-12-(2-allyl-4-(butan-2-one)phenyl)ethynyl]-quinuclidin-3-ol (0.3 g) in ethanol (10 ml), sodium acetate (0.085 g) and 0-ethylhydroxylamine hydrochloride (0.1 g) was heated at reflux for 16 hours.
The mixture mixture was cooled and the solvent removed by evaporation. The residue was triturated with a 80:20:3 (v/v~v) mixture of ethyl acetate/ethanol/triethylamine. The residue was purified by dry flash chromatography on 60H silica (Herck Art. No. 7736) using a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give 3-12-(2-allyl-4-(3-ethoxyimino)butyl)ethynyl]quinuclidin-3-ol as an oil (0.22 g), microanalysis found; C, 73.5; H, 8.8; N, 7.2X;
C24H32N202.3/4H20 requires C, 73.2; H, 8.6; N, 7.1Z; m/z = 381 (H+H).

E~XPLL 102 Sodium borohydride (0.016 g) was added to a suspension of 3-12-(2-allyl-4-(butan-2-one)-phenyl)ethynyllquinuclidin-3-ol (0.2 g)~ in ethanol (5 ml) at 0C under an atmosphere of argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours.
The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (10 ml) and water (10 ml). The W O 94/25459 21~ 0 7 3 ~ PCT/GB94/00910 aqueous mixture was extracted with ethyl acetate (3 x 15 ml). The ethyl acetate extracts were combined, dried (MgS04), and evaporated to give an oil, which was purified by flash chromatography on silica gel using a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give 3-[2-(2-allyl-4-(3-hydroxybutyl)phenyl)ethynyl]quinuclidin-3-ol as a.colourless oil (0.155 g), microanalysis found: C, 73.3; H, 8.7; N, 3.6; C22H29N02.1.2H H20 requires C, 73.2; H, 8.8; N, 3.9; m/z = 340 (H+H).

Using a similar procedure to that described in Example 11 but using 3-(4-bromobenzyloxymethoxy)propane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane there was obtained 3-[2-(4-(3-methoxypropoxy)methyl)phenyl)ethynyllquinuclidin-3-ol as a solid, m.p. 121-122C; NHR: 1.2-1.4(1H, m), 1.5-1.65(1H, m), 1.7-1.85(2H, q), 1.85-2.0(3H, m), 2.6-2.7(4H, t), 2.8-2.9(1H, d), 3.0-3.1(1H, d), 3.2(3H, s), 3.35-3.45(2H, t), 3.45-3.55(2H, t), 4.45(2H, s), 5.5(1H, s), 7.25-7.35(2H, d) and 7.35-7.45(2H, d).
The starting material was prepared using an analogous procedure to that described in examples 11 for the preparation of 1-(4-bromobenzyloxy-2-methoxyethane but starting from 3-methoxypropanol.
There was thus obtained 3-(4-bromobenzyloxymethoxy)propane;
NHR (CDCl3): 1.85-1.95(2H, q), 3.35(3H, s), 3.45-3.50(2H, t), 3.5-3.55(2H, t), 4.5(2H, s), 7.2-7.3(2H, d) and 7.4-7.5(2H, d).

~AnPLE 104 Using a similar procedure to that described in Example 11 but using 2-(4-bromobenzyloxy)-1-(isopropoxy)ethane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane there was obtained 3-[2-(4-(2-isopropoxyethoxy)methyl)phenyl)ethynyl]quinuclidin-3-ol as a solid, m.p. 117-118C; NHR: 1.05-1.1(6H, d), 1.2-1.4(1H, m), 1.5-1.7(1H, m), 1.8-2.0(3H, m), 2.6-2.75(4H, t), 2.8-2.9(1H, d), 3.0(3.1(1H, d), 3.5-3.6(5H, m), 4.5(2H, s), 5.55(1H, s) and 7.25-7.4(4H, q) -The starting material was prepared using an analogous procedure to that described in Example 11 for the preparation of W O 94/25459 21 ~ ~ 7 ~ ~ PCT/GB94/00910 1-(4-bromobenzyloxy)-2-methoxyethane but starting from isopropoxy ethanol. There was thus obtained 2-(4-bromobenzyloxy)-1-(isopropoxy)ethane; NHR (CDC13)~ 1.2(6H, d), 3.6(5H, m), 4.5(2H, s), 7.2-7.3(2H, d), and 7.4-7.5(2H, d).

Using a similar procedure to that described in Example 11 but using 3-(4-bromophenyl)-1-(methoxy)propane as starting material in place of l-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane there was obtained 3-12-(4-(3-methoxypropyl)phenyl)ethynyllquinuclidin-3-ol as a solid, m.p.
145C; NHR: 1.2-1.4(1H, m), 1.5-1.7(1H, m), 1.7-2.0(5H, m), 2.55-2.75(6H, m), 2.75-2.9(1H, d), 3.0-3.15(1H, d), 3.2(3H, s), 3.25-3.4(2H, m), 5.5(1H, s), 7.1-7.2(2H, d) and 7.25-7.74(2H, d).
The starting material was prepared using an analogous procedure to that described in Example 35 for the preparation of 3-(4-allyloxyphenyl)-1-methoxypropane but starting from 3-(4-bromophenyl)propyl bromide. There was thus obtained 3-(4-bromophenyl)-1-(methoxy)propane; NHR (CDC13): 1.8-2.0(2H, m), 2.6-2.7(2H, t), 3.3-3.4(5H, m), 7.0-7.1(2H, d) and 7.3-7.4(2H, d).

E~AnPL~ 106 Using a similar procedure to that described in Example 11 but using 3-(4-bromobenzyloxy)propane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there was obtained 3-12-(4-propoxymethylphenyl)ethynyl]quinuclidin-3-ol as a solid, m.p.
140-141C; NHR (CDC13): 0.9-1.0(3H, t), 1.3-1.5(1H, m), 1.55-1.7(3H, m), 1.9-2.1(3H, m), 2.7-2.95(5H, m), 3.0-3.1(1H, d), 3.25-3.35(1H, d), 3.4-3.5(2H, t), 4.5(2H, s), 7.2-7.3(2H, d) and 7.35-7.43(2H, d).
The starting material was prepared using an analogous procedure to that described in Example 11 for the preparation of 1-(4-bromobenzyloxy)-2-methoxyethane but starting from n-propanol. There was thus obtained 3-(4-bromobenzyloxy)propane; NHR (CDC13): 0.9-1.0(3H, t), 1.6-1.7(2H, q), 3.4-3.5(2H, t), 4.5(2H, s), 7.15-7.3(2H, d) and 7.4-7.5(2H, d).

2 ~
W O 94l25459 PCT/GB94/00910 ~A~PL~ 107 Using a similar procedure to that described in Example 11 but with 1-(4-bromo-2-fluorobenzyloxy)-2-methoxyethane in place of 1-(4-bromobenzyloxy)-2-methoxyethane there was obtained 3-l2-(4-~2-methoxyethoxymethyl}-2-fluorophenyl)ethynyllquinuclidin-3-ol (13X yield) as a solid, m.p. 117-118C; microanalysis, found: C, 68.4; H, 7-5; N, 4.3X; ClgH24FNO3 requires: C, 68.4; H, 7.3; N, 4.2Z; NHR:
1.30(1H, m), 1.61(1H, m), 1.95(3H, m), 2.69(4H, t), 2.83(1H, d), 3.07(1H, d), 3.25(3H, s), 3.49(2H, m), 3.56(2H, m), 4.52(2H, s), 5.66(1H, s), 7.22(2H, m) and 7.39(1H, t); m/Z 333 (H+H).
The 1-(4-bromo-2-fluorobenzyloxy)-2-methoxyethane used as starting material was obtained as follows.
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60Z mineral oil suspension) in DHF (200 ml) at room temperature and under a atmosphere of argon. The stirred mixture was heated to 60C and then cooled to 5C. A solution of 4-bromo-2-fluorobenzyl bromide (15 g) in dichlorobenzene (75 ml) was added over 15 minutes. The mixture stirred for 12 hours at room temperature, then for 1 hour at 60C and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3 x 200 ml).
The combined extracts were washed with 2n hydrochloric acid (100 ml), water (2 x 100 ml), saturated brine (100 ml) and dried (HgSO4).
Evaporation of the solvents gave an oil which was distilled using a short path distillation apparatus to give 1-(4-bromo-2-fluorobenzyloxy)-2-methyoxyethane (11.6 g), furnace temperature 125C/0.01 bar; NMR (CDCl3):
3.40(3H, s), 3.5-3.7(4H, m), 4.58(2H, s) and 7.2-7.4(3H, m).

E~AXPLE 108 Sodium borohydride (1.14g) was added portionwise over a period of 10 minutes to a solution of 3-~-2-{2-formyl-4-ethoxycarbonyl-ethylphenyl}ethynyllquinuclidin-3-ol (2 g) and saturated aqueous sodium bicarbonate (2 ml) in methanol (1Oml) at 10C under an atmosphere of argon. The reaction mixture was stirred at ambient temperature 2 hours.
An equal volume of water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4), evaporated and the residue was purified by chromatography on silica gel (Varian Bond W O 94/25459 21 ~ ~ 7 9 ~ PCT/GB94/00910 Elut Sl silica gel) using a gradient of 0 to 20% ethyl acetate in hexane to give 3-[2-~2-hydroxymethyl-4-ethoxycarbonylethylphenyl}-ethynyllquinuclidin -3-ol borane complex (480 mg) as a solid; NMR:
2.65(2H, t), 2.95(6H, m), 3.2(1H, d), 3.3(1H, s), 3.4(1H, d), 3.65(1H, s), 4.73(2H, s), 7.1(1H, m), 7.28(1H, s), 7.35(1H, d); m/Z 358 (H+H).

E~A~PLE 109 Using the method described in Example 70, but with 4-(2-iodophenoxy)-2-methylbut-2-ene (855 mg) in place of 2-iodophenylacetonitrile and (+) 3-ethynyl-3-hydroxyquinuclidine in place of 3-ethynyl-3-hydroxyquinuclidine there was thus obtained 3-[2-~2-(3-methylbutox-2-ene)phenyl}ethynyllquinuclidin-3-ol (427 mg) as a solid, m.p 175.1C, microanalysis, found: C, 76.4; H, 8.3; N, 4.7X;
C20H25N02 O.lSH20 requires: C, 76.5; H, 8.12; N, 4.46Z; NHR 1.31(1H, m), 1.55(1H, m), 1.74(6H, d), 1.81-2.14(3H, m), 2.67(4H, t), 2.81(1H, d), 3.08(1H, d), 4.57(2H, d), 5.37-5.55(2H, m), 6.9(1H, t), 7.03(1H, d) and 7.29(2H, m); m/Z 312 (H+H).

E~AnPL~ 110 Using the method described in Example 1, but carrying out the reaction at ambient temperature overnight and ~ith 2,2-dichloroethyl-2-iodobenzoate [generated in situe by the reaction of 2-iodobenzoyl chloride (718 mg) with 2,2-dichloroethanol (0.34 ml) in triethylamine (1 ml) as solvent at ambient temperaturel in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thus obtained 3-[2-(2-(2',2'-dichloroethoxycarbonyl)phenyl}-ethynyllquinuclidin-3-ol as a solid (396 mg), m.p. 160.7C;
microanalysis, found: C, 57.9: H, 5.3; N, 4.1-/.; C18H19C12N03 0.25H20 requires C, 58.0; H, 5.27; N, 3.76-~; NHR: 1.31(1H, m), 1.6(1H, m), 1.98(3H, m), 2.6-3.05(6H, m), 4.72(2H, d~, 5.58(1H, s), 6.6(1H, t), 7.45-7.68(3H, m), 7.92(1H, d); m/Z 368C.

EgAnPLE 111 Using the method described in Example 1, but carrying out the reaction at ambient temperature overnight and ~ith 2-chloroethanol-2-iodobenzate Igenerated in situ by the reaction of 21~)7~

2-iodobenzoyl chloride (718 mg) with 2-chloroethanol (0.34 ml) in triethylamine (1 ml) as solvent at ambient temperature)] in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thus obtained 3-l2-12-(2-chloroethoxycarbonyl)phenyl}-ethynyl]quinuclidin-3-ol as a solid (286 mg), m.p. 132.2C;
microanalysis, found C, 63.8; H, 6.1; N, 4.5%; C18H20ClN03, 0.25H20 requires C, 63.9; H, 6.11; N, 4.14Z; NHR: 1.32(1H, m), 1.57(1H, m), 1.94(3H, m), 2.7(4H, m), 3.05-3.4(2H, m), 3.95(2H, m), 4.51(2H, m), 5.56(1H, s), 7.44-7.65(3H, m), 7.88(1H, d); m/Z 334 (H+H).

E~nPLL 112 Using the method described in Example 1, but carrying out the reaction at ambient temperature overnight and with phenyl-2-iodobenzoate, generated in situ by the reaction of 2-iodo benzoyl chloride (678 mg) ~ith phenol (279 mg) in triethylamine (1 ml) as solvent at ambient temperature)] in place of ethyl 3-(3-allyl-4-trifluoromethyl-sulphonoxyphenyl)propionate there ~as thus obtained 3-l2-~2-(phenoxycarbonyl)phenyl}ethynyllquinuclidin-3-ol as a solid (472.5 mg), m.p. 60.3C, microanalysis, found: C, 71.4; H, 5.8; N, 3.9;
I, 2.8X; C22H21N030.75H20Ø07 HI requires C, 71.4; H, 61.5; N, 3.79; I, 2.4X; NnR: 1.3(1H, m), 1.5(1H, m), 1.9(3H, m), 2.67(4H, t), 2.95(1H, +H20), 3.14(1H, d), 5.15(1H, s), 7.25-7.7(8H, m), 8.03(1H, d); m/Z 348 (~+H).

E~nPL~ 113 Using the method described in Example 1, but carrying out the reaction at ambient temperature overnight and ~ith 2,2,2-trichloroethyl-2-iodobenzoate Igenerated in situe by the reaction of 2-iodo benzoyl chloride (718 mg) with 2,2,2-trichloroethanol (0.34 ml) in triethylamine (1 ml) as solvent at ambient temperature) in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there ~as thus obtained 3-l2-{2-(2,2,2trichloroethoxycarbonyl)-phenyl}ethynyl]quinuclidin-3-ol as a solid (533 mg), m.p. 127.4C;
microanalysis, found C, 53.4; H, 4.6; N, 3.4%; C18H18Cl3N03 requires C, 53.7; H, 4.51; N, 3.48%; NMR: 1.3(1H, m), 1.53(1H, m), 1.95(3H, m), W O 94/25459 ~ ~ ~ PCT/GB94/00910 2.68(4H, t), 2.82(1H, d), 3.13(1H, d), 5.14(2H, s), 5.57(1H, s), 7.5-7.7(3H, m), 7.98(1H, d); m/Z 404 (H+H).

E~nPLE 114 A mixture of 3-12-{2-hydroxymethyl-4-ethoxycarbonylethylphenyl}ethynyl]quinuclidin-3-ol borane complex (400 mg), triphenylphosphine (524 mg) and toluene (50 ml) was stirred at 0C
under an atmosphere of argon. A solution of diethylazodicarboxylate (340 mg) in toluene (10 ml) was added over a period of 5 minutes and the reaction mixture stirred at ambient temperature overnight. Water (50 ml) was added and the mixture extracted with ethyl acetate. The ethyl acetate extracts were dried (HgS04) and evaporated. The residue was purified by chromatography on silica gel (Yarian Band Elut Sl silca gel) using a gradient of 0 to 20X ethyl acetate in hexane to give the product as a borane complex. Treatment at 10C with hydrochloric acid dissolved in a mixture of acetone and ethanol gave, upon evaporation, 3-12-{2-phenoxymethyl-4-ethoxycarbonylethylphenyl}ethynyllquinuclidin -3-ol as a gum; NnR (CDC13): 1.24(3H, t), 2.6(2H, t), 2.96(2H, t), 4.1(2H, q), 5.08( H, s), 6.9-7.05(4H, m), 7.15-7.45(5H, m); m/Z 434 (H+H).

E~A~PLE 115 In a similar manner to that described in Example 1 but using 3-ethynyl-3-hydroxyquinuclidine and methyl 6-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)caproate as starting materials, there was thus obtained 3-12-allyl-6-(4-methoxycarbonyl-pentyl)ethynyllquinuclidin-3-ol as a gum (87mg), NHR: 1.25-1.5(1H,m), 1.5-1.9(1H+H20,m), 1.9-2.1(1H,m), 2.2-2.3(2H,t), 2.5-2.6(2H,t), 2.7-3.0(4H,m), 3.0-3.1(1H,d), 3.3-3.4(1H,dd), 3.45-3.55(2H,d), 3.65(3H,s), 5.0-5.1(2H,m), 5.9-6.1(1H,m), 6.95-7.0(2H,m) and 7.3-7.35(1H,d), m/z 396(M+H).
The methyl 6-(3-allyl-4-trifluoromethylsulphonyloxy-phenyl)caproate used as starting material was prepared in a similar manner to ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (described in Example 1).

W 0 94/2~4~9 21~ ~ 7 ~ ~ PCT/GB94/00910 ~XAnPL~ 116 In a similar manner to that described in Example 1 but using 3-allyl-4-trifluoromethylsulphonyloxyphenylpropionate as starting material there ~as thus obtained 3-[2-allyl-3(4-propionitrile)-ethynyllquinuclidin-3-ol as a solid (478mg), m.p. 124.3C; NHR (CDCl3):
1.3-1.45(1H,m), 1.5-1.65(1H,m), 1.8-2.1(3H,m), 2.5-2.6(2H,t), 2.7-2.9(5H,m), 2.9-3.05(1H,d), 3.2-3.3(1H,dd), 3.4-3.5(2H,d), 4.95-5.1(2H,m), 5.8-6.0(1H,m), 6.9-7.0, (2H,m), and 7.3-7.35(1H,d), m/z 321(H+H)-The 3-allyl-4-trifluoromethylsulphonyloxyphenylproprionitrile used as starting material was prepared in a similar manner to ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionte described in Example 1.

~U~PL~ 117 A solution of 3-12-(2-allyl-4-(2-ethoxycarbonylethyl)-phenyl}ethynyllquinuclidin-3-ol (l.Og) in methanol saturated with ammonia ~as allowed to stand at ambient temperature for 48 hours. The solvent ~as evaporated to give an oil ~hich, on trituration ~ith diethyl ether, gave a solid. The solid was crystallised from ethyl acetate to give 3-~2-{2-allyl-4-(2-amidoethyl)phenyl}ethynyl]quinuclidin-3-ol as a solid (562mg), m.p. 137.5C; microanalysis, found: C, 72.6; H, 7.70; N, 7.80%, C21H26N202. 0.5 H20 requires: C, 72.6; H, 7.77; N, 8.00-~; NMR:
1.28-1.45(1H,m), 1.50-1.85(1H,m), 1.85-2.12(3H,m), 2.30(2H,t), 2.75(10H,m), 5.05(2H,m), 5.60(1H,bs), 5.88-6.05(1H,m), 6.70(1H,bs), 7.03(2H,m) and 7.25(2H, d and bs), m/z 339(H+H).

~AXPL~ 118 The procedure described in Example 117 was repeated using methanolic methylamine in place of methanolic ammonia. There ~as thus obtained, after crystallisation from ethyl acetate, 3-[2-{2-allyl-4-(2-methylamidoethyl)phenyl}ethynyllquinuclidin-3-ol as a solid, m.p. 115.2C; microanalysis, found: C, 72.1; H, 8.30; N, 7.80%, C22H28N20. 0.75H20 requires: C,72.2; H, 7.66; N, 7.66-~;
N~R(ICD3]2SO/CD3COOD): 1.62-1.82(lH,m), 1.92-2.10(lH,m), 2.10-2.30(3H,m), W O 94/25459 21~ 0 7 ~ ~ PCT/GB94/00910 2.38(2H,t), 2.60(3H,s), 2.82(2H,t), 3.00-3.47(6H,m), 3.50(2H,d), 5.05(2H,m), 5.90-6.05(1H,m), 7.05(2H,m) and 7.30(1H,d), m/z 353(H+H).

~AnPL~ 119 A solution of 3-[2-(2-allyl-4-(2-ethoxycarbonylethyl)-phenyl}ethynyllquinuclidin-3-ol (734mg) in tetrahydrofuran (15ml) ~as added over a period of 0.25 hours to a stirred suspension of lithium borohydride (450mg) in tetrahydrofuran (15ml) at 0C under an atmosphere of argon. The mixture was stirred for 16 hours at ambient temperature.
The tetrahydrofuran ~as removed by evaporation. Acetone (20ml) ~as added slo~ly ~ith stirring followed by lH aqueous hydrochloric acid (20ml).
The mixture ~as stirred for 1 hour at ambient temperature. The acetone ~as removed by evaporation and the aqueous mixture ~as basified to pH12 using 2H aqueous sodium hydroxide solution and then extracted with ethyl acetate (2 x 50ml). The ethyl acetate extracts ~ere combined, washed ~ith brine (2 x 30ml), dried (HgS04) and evaporated. The residue ~as purified by flash column chromatography on Neutral Alumina (ICN Alumma N
32-63) using a 9:1 (v/v) mixture of ethyl acetate and methanol as eluent to give 3-[2-(2-allyl-4-(3-hydroxypropane)phenyl}ethynyllquinuclidin-3-ol (123mg) as a glass; NHR(CDCl3): 1.35-1.52(1H,m), 1.58-1.73(1H,m), 1.87(2H,m), 1.92-2.22(3H,m), 2.68(2H,t), 2.77-2.98(4H,m), 3.08(1H,d), 3.32(1H,d.d), 3.50(2H,d), 3.63(2H,t), 4.98-5.12(2H,m), 5.85-6.08(1H,m), 7.01(2H,m) and 7.33(1H,d): m/z 326(H+H).

E~AXrLE 120 Using the method described in Example 67 but using 3-[2-(2-allyl-4-(2-methoxycarbonylpropyl)phenyl}ethynyllquinuclidin-3-ol in place of 3-[2[2-allyl-4-(2-ethoxycarbonylethyl)phenyllethynyll-quinuclidin-3-ol, there ~as obtained 3-[2-l2-allyl-4-(2-carboxypropyl)phenyl]ethynyllquinuclidin-3-ol hydrochloride salt as a solid, m.p. 45-47C (dec), NHR([CD3]2S0/CD3COOD): 1-10(3H,d), 1.75-1.90(1H,m), 1.95-2.10(1H,m), 2.13-2.41(3H,m), 2.62(2H,m), 2.93(1H,q), 3.15-3.33(4H,m), 3.40(1H,d), 3.51(2H,d), 3.60(1H,d), 4.98-5.10(2H,m), 5.88-6.08(1H,m), 7.08(2H,m) and 7.37(1H,d), m/z 354(~+H)-W 0 94/25459 21~ O ~ ~ ~ PCT/GB94/00910 E~AHPLE 121 Cuprous Iodide (lSOmg) and tris-(dibenzylidene acetone)dipalladium (O) (100mg) were added to a solution of 3-((E)-2-tributylstannyl-1-ethenyl)-3-hydroxyquinuclidine (882mg), and N-(1-butyl)-4-iodophenylacetamide (951mg) in DHF (lOml) under an atmosphere of argon. The reaction mixture was stirred at ambient temperature for 15 minutes. The solvent was removed by evaporation, and the residue was purifed by chromatography on silica gel using 20%
methanol in dichloromethane containing lX ammonia as eluent to give 3-[(E)-2-[4-[N-(1-butyl)-carboxamidomethyl]phenyl]vinyl]quinuclidin-3-ol, as a solid which ~as recrystallised from ethyl acetate to give a solid (330mg), mpt: 128-130C; microanalysis, found: C:71.6; H: 8.6; N:7.7X;
C21H30N202 + 0.15 CH3C02C2H5 + 0.10 H20 requires: C: 72.0; H: 8.6; N:
7.8~; NMR: 0.93-0.90, (3H,t), 1.15-1.55,(6H,m), 1.57-1.75(2H,m), 1.93-2.10(H.bm), 2.55-2.82(5H,m), 2.85-2.90(1H,dd), 3.00-3.08(2H,q), 3.35(2H,s), 4.72(1H,s), 6.50-6.63(2H,AB), 7.18-7.38(4H,AB) and 7.90(H,bt); m/z343(H+H).
The N-(1-butyl)-4-iodophenylacetamide used as starting material ~as prepared as follo~s.
1-Butylamine (1.83g) was added to a solution of 4-iodophenylacetyl chloride (2.80g) in ether (25ml), and the reaction mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was then partitioned between water (30ml) and ethyl acetate (50ml). The organic layer was washed with 2H aqueous hydrochloric acid (25ml), water (30ml), brine (25ml), dried (ngS04), and evaporated to give N-l-butyl, (4-iodophenyl)acetamide, as a colourless crystalline solid, (2.9g), mp.: 100-102C, NHR: 0.82-0.88(3H,t), 1.18-1.43(4H,m), 3.00-3.06(2H,q), 3.35(2H,s), 7.03-7.67(4H,AB), 7.97(H,bt); m/z 318 (M+H).

~AnPLE 122 In a similar manner to Example 121, but usin~
4-iodophenylacetamide in place of N-(1-butyl)-4-iodophenylacetamide, there was obtained 3-1(E)-2-(4-carboxamidomethylphenyl)vinyl]-quinuclidin-3-ol as a solid, m.p. 180-184C, (after recrystallisation from a mixture of ethyl acetate/hexane), microanalysis, Found: C, 69.7;
H 8.1; N, 9.5%; C17H22N202 0.5 H20 requires: C, 69-3; H:7-8; N:9-5% m/z WO 94/25459 21~ ~ 7 ~ ~ PCT/GB94/00910 287 (H+H); NMR: 1.17-1.53(2H,m), 1.60-1.75(2H,m), 1.92-2.08(H,m), 2.55-2.82(5H,m), 2.85-2.90(1H,d), 3.33(2H,s), 4.72(H,s), 6.50-6.63(2H,AB) and 6.82(H,b).
The 4-iodophenylacetamide used as starting material was obtained as follows.
Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of 4-iodophenylacetic acid (26.2g), in dichloromethane (150ml).
The reaction mixture was stirred at ambient temperature for 18 hours and the solvent removed by evaporation to give 4-iodophenylacetyl chloride as an oil (23g) which was purified by vacuum distillation; b.p. 118 - 119C
(0.35mm~g) Concentrated aqueous ammonia (density, 0.88g/cm3) ~as added to a solution of 4-iodophenylacetyl chloride (2.80g) in ether (30ml) and the mixture was stirred at ambient temperature for 15 minutes. The product, 4-iodophenylacetamide, was obtained as a colourless crystalline solid (2.36g), m.p: 200-204C; NMR: 3.34(2H,s), 6.87(H,bs), 7.44(2H,bs), 7.04-7.68(4H,AB); m/z 262(M+H).

~AXPLE 123 In a similar manner to Example 121, but using methyl (4-iodophenyl)acetate in place of N-(1-butyl)-4-iodophenylacetamide, there was obtained 3-1(E)-2-(4-methoxycarbonylmethylphenyl)-vinyl]quinuclidin-3-ol as a solid (135mg), mp 133-136C (after recrystallisation from ethyl acetate), NnR: 1.12-1.55(2H,m), 1.67(2H,m), 2.00(H,bm), 2.58-2.90(6H,m), 3.30(2H,s), 3.60(H,s), 3.64(2H,s), 4.73(H,s), 6.57(2H,s), 7.17-7.40(4H,AB).
The methyl 4-iodophenylacetate used as starting material was prepared as follows.
4-iodophenylacetyl chloride (2.80g) was added to methanol (10ml) and the mixture stirred at ambient temperature for 15 minutes.
The solvent was removed by evaporation to give methyl 4-iodophenylacetate as a red oil (2.73g) which was used without further purification; NHR:
3.62(s,3H), 3.67(s,2H), 7.05-7.70(AB,4H). m/z277(M+H) .

W o 94/25459 216 ~ ~ ~ a PCT/GB94100910 E~A~PLE 124 The procedure used in Example 93 was repeated using 3-[4-(3-hydroxypropyl)phenoxymethyllquinuclidin-3-ol borane complex (0.24g) instead of 3-(4-cyanomethylphenoxymethyl)quinuclidin-3-ol borane complex, except that the reaction mixture was diluted with an equal volume of diethyl ether and stirred for 16 hours to give 3-14-(3-hydroxypropyl)phenoxymethyl]quinuclidin-3-ol hydrochloride (0.17g) as a colourless solid, m.p. 143-146C; microanalysis, found:
C, 62.4; H, 8.0; N, 4.4X; C17H25N03 HCl requires: C, 62.3; H, 8.0; N, 4.3%; N~R: 1.5-2.0(5H,m), 2.1-2.3(2H,m), 2.4-2.6(2H,t), 2.9-3.4(6H,m), 3.35-3.5(2H,t), 3.9-4.1(2H,s), 4.2-4.6(1H,br), 5.4-5.6(1H,s), 6.8-6.95(2H,d), 7.05-7.2(2H,d)and 10.4-10.8(1H,s); m/z 292 (H+H).
The 3-14-(3-hydroxypropyl)phenoxymethyl]quinuclidin-3-ol borane complex used as starting material was prepared from 3-(4-hydroxyphenyl)-1-propanol using an analogous procedure to that described in Example 93 for the preparation of the borane starting material. Thus, the procedure described in Example 93 was repeated using 3-(4-hydroxyphenyl)-1-propanol (0.30g) instead of 4-hydroxybenzyl cyanide. There was thus obtained 3-14-(3-hydroxypropyl)phenoxymethyl]quinuclidin-3-ol borane complex (0.25g) as a solid.

ESA~PL~ 125 Using the method described in Example 1, but with methyl 3-(3-allyl-4-trifluromethylsulphonyloxyphenyl)-2,2-dimethylpropionate in place of ethyl 3-(3-allyl-4-trifluromethylsulphonyloxyphenyl) propionate, there was thus obtained 3-12-(2-allyl-4-(2-methoxy-carbonyl-2,2-dimethylethyl)phenyl)ethynyl]quinuclidin-3-ol as an oil;
NnR (CDC13): 1.15(6H,s), 1.32-1.50(1H,m), 1.57-1.77(1H,m), 1.90-2.10(3H,m), 2.30(1H,m), 2.70-3.00(6H,m), 3.05(1H,d), 3.31(1H,dd), 3.50(2H,d), 3.62(3H,s), 4.97-5.12(2H,m), 5.88-6.03(lH,m), 6.90(2H,m) and 7.30(lH,d); m/z 482(H+H).
The methyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-2,2-dimethylpropionate used as starting material was obtained as follows.

W O 94/25459 ~16 0 7 9 ~ PCT/GB94/00910 Allyl bromide (0.66ml) was added to a stirred suspension of methyl 2,2-dimethyl-3-(4-hydroxyphenyl)propionate (1.41g) and potassium carbonate (1.08g) in butan-2-one (12ml). The reaction mixture was heated at reflux for 19 hours, cooled, and filtered. The filtrate was evaporated to give methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate (1.59g) as an oil; NHR(CDC13): 1.17(6H,s), 2.78(2H,s), 3.65(3H,s), 4.50(2H,m), 5.33(2H,m), 6.02(1H,m), 6.70(2H,m) and 7.00(2H,m); m/z 248(H+).
A solution of methyl 2,2-dimethyl-3-(4-allyloxyphenyl)-propionate (1.56g) in diphenyl ether was heated at reflux for 15 minutes. The reaction mixture was cooled to ambient temperature and the reaction mixture was filtered through a silica gel pad. Elution with a 4:1 (vtv) mixture of hexane and ethyl acetate gave methyl 2,2-dimethyl-3-(3-allyl-4-hydroxyphenyl)propionate (1.53g) as a yellow oil; microanalysis, found: C, 72.2; H, 7.80X; C15H2003 requires: C, 72.6; H, 8.12Z; NHR(CDC13): 1.15(6H,s), 2.73(2H,s), 3.35(2H,m), 3.63(3H,s), 4.87(1H,s), 5.10(2H,m), 5.95(1H,m), 6.67(1H,m) and 6.83(2H,m); m/z 249 (H+H).
Trifluoromethane sulphonic anhydride (1.25ml) was added to a stirred solution of methyl 2,2-dimethyl-3-(3-allyl-4-hydroxyphenyl)propionate (1.51g) in pyridine (6.0ml) at 0 under an atmosphere of argon. After 16 hours lH hydrochloric acid (lOOml) was added to the reaction mixture and the mixture was extracted with ether. The ether phase was washed with brine, dried and evaporated to give an oil. Purification of the oil by chromatography on silica gel using a 9:1 (v/v) mixture of hexane/ethyl acetate mixture as eluent give methyl 2,2-dimethyl-3-(3-allyl-4-trifluoromethyl-sulphonyloxy)phenyl)propionate (2.18g) as an oil; NHR(CDC13) 1.18(6H,s), 2.82(2H,s), 3.42(2H,d), 3.63(3H,s), 5.10(2H,m), 5.92(1H,m), 7.02(2H,m) and 7.13(1H,d).

EXAnPLE 126 Using the method described in Example 1, but with methoxyethyl 2-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-propionate in place of ethyl 3-(3-allyl-4-trifluoromethyl-sulphonyloxyphenyl)propionate and (-)-3-ethynyl-3-hydroxy-quinuclidine ~1~ û79 ~

in place of (+)-3-ethynyl-3-hydroxyquinuclidine there was thus obtained (-) 3-[2-(2-allyl-4-methoxyethoxycarbonyl-1-methylethyl-phenyl)ethynyllquinculidin-3-ol (as a diastereoisomic pair) as a yellow oil; microanalysis, found: C, 71.0; H, 8.20; N, 3.10X;
C25H33N04. 0.5 H20 requires C, 71.3; H, 8.10; N, 3.30%; NnR(CDC13) 1.13(3H,d), 1.41(1H,m), 1.64(1H,m), 2.06(3H,m)j 2.75(8H,m), 3.30(4H,m), 3.52(4H,m), 4.18(2H,m), 5.06(2H,m), 5.94(1H,m), 6.98(2H,m) and 7.31(1H,d); m/z 412(H+H).
The methoxyethyl 2-methyl-3-(3-allyl-4-trifluromethyl-sulphonyloxyphenyl)propionate used as starting material was prepared as follows.
Concentrated sulphuric acid (0.2ml) was added to a stirred suspension of 4-oxypropionyl-2-methylcinnamic acid (2.78g) in 2-methoxyethanol (20ml) and the reaction mixture was heated at 100C
for 16hours. The 2-methoxyethanol ~as removed by evaporation and saturated sodium bicarbonate solution (20ml) was added. The mixture was extracted with ether. The ether phase ~as dried (HgS04) and evaporated to give methoxyethyl 3-(4-hydroxyphenyl)-2-methyl cinnamate (2.60g) as a colourless solid m.p.101.8C; NHR(CDC13): 2.12(3H,d), 3.44(3H,s), 3.72(2H,t), 4.38(2H,t), 5.82(1H,m), 6.82(2H,m), 7.28(2H,d) and 7.6(lH,s).
A solution of methoxyethyl 2-methyl 4-hydroxycinnamate (2.56g) in ethyl acetate (75ml) was hydrogenated at atmospheric pressure and ambient temperature over a 10~ Pd-C catalyst (180mg).
The catalyst was removed by filtration and the filtrate ~as evaporated to give methoxyethyl 2-methyl-3-(4-hydroxyphenyl)propionate (2.56g) as an oil; N~R(CDC13): 1.17(3H,d), 2.70(2H,m), 2.92(1H,q), 3.36(3H,s), 3.55(2H,m), 4.21(2H,m), 5.16(1H,bs), 6.72(2H,m) and 7.01(2H,m).
hethoxyethyl 2-methyl-3-(4-allyloxyphenyl)propionate was prepared using the procedure used to prepare ethyl 3-(4-allyloxy-phenyl)propionate (see Example 1). ~ethoxyethyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate was prepared from methoxyethyl 2-methyl-3-(4-allyloxyphenyl)propionate using the method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-hydroxyphenyl)-propionate. The product was isolated as a yellow oil; microanalysis;

W O 94/25459 21 fi ~ 7 3 ~ PCT/GB94/00910 found: C, 69 0 H, 7.70%; C16H2204 requires C, 69.0 H. 7.97X; m/z 279 (H+H).
The method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate was used to convert methoxyethyl 2-methyl-3-(3-allyl-4-hydroxy-phenyl)propionate to methoxyethyl 2-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate; NhR(CDCl3): 1.18(3H,d), 2.73(2H,m), 3.00(1H,q), 3.36(3H,s), 3.42(2H,d), 3.51(2H,m), 4.18(2H,m), 5.09(2H,m), 5.90(1H,m) and 7.13(3H,m); m/z 411 (H+H).

E~A~PLE 127 Using the method described in Example 1 but using (+) 3-ethynyl-3-hydroxy quinuclidine in place of (+)3-ethynyl-3-hydroxy quinuclidine and methoxyethyl 2-methyl-3-(3-allyl-4-trifluoromethyl sulphonyloxyphenyl)propionate in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate there was thus obtained (as a diastereomeric pair) (+) 3-[2-(2-allyl-4-methoxy ethoxycarbonyl-1-methylethylphenyl)ethynyl]quinuclidin-3-ol as an oil; NHR(CDCl3): 1.16(3H,d), 1.44(1H,m), 1.64(1H,m), 2.05(3H,m), 2.87(8H,m), 3.38(4H,m), 3.52(4H,m), 4.18(2H,m), 5.05(2H,m), 5.94(1H,m), 6.98(2H,m) and 7.31(1H,d); m/z 412 (H+H).

Using the method described in Example 1 but using ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1-methyl propionate in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxy-phenyl)propionate, there was thus obtained 3-[2-(2-allyl-4-(2-ethoxycarbonyl-1-methylethyl)phenyl)ethynyl~quinuclidin-3-ol as a gum, NHR(CDCl3): 1.18(3H,t), 1.30t2H,d), 1.45(1H,m), 1.65(1H,m), 2.02(3H,m), 2.20(1H,m), 2.53(2H,m), 2.87(4H,m), 3.06(1H,d), 3.22(1H,m), 3.30(1H,d.d), 3.50(2H,d), 4.07(2H,q), 5.05(2H,m), 5.95(1H,m), 7.02(2H,m) and 7.33(1H,d); m/z 382(H+H).
The compound of formula 2 (Z = OS02CF3) used as starting material was prepared as follows.
Triethyl phosphonacetate (5.0g) was added to a stirred suspension of sodium hydride (0.95g; 60% dispersion in oil) in THF

216~735 (35ml) at ambient temperature under an atmosphere of argon. After 1 hour, a solution of 4-benzyloxyacetophenone (5.0g) in tetrahydrofuran (35ml) was added. The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and water (200ml) was added. The aqueous mixture was extracted with ether. The ether phase was washed with water, brine, dried (~gS04) and evaporated. The residue was purified on silica gel using a 19:1 (v/v) mixture as eluent to give ethyl 3-methyl-3-(4-benzyloxy)phenyl cinnamate (3.44g) as a colourless solid; NHR (CDCl3): 1.31(3H,t), 2.52(3H,s), 4.20(2H,q), 5.08(2H,s), 5.95(1H,m), 6.93(2H,m) and 7.40(7H,m); m/z 297(H+H).
Ethyl 3-(4-benzyloxyphenyl)but-2-enoate (3.4g) in ethyl acetate (lOOml) was hydrogenated over a 10% palladium-on-carbon catalyst (250mg) at atmospheric pressure/ambient temperature. The catalyst was removed by filtration and the filtrate evaporated to give an oil. The oil was purified by chromatography on silica gel using a 4/1 (v/v) mixture of hexane and ethyl acetate as eluent to give ethyl 3-(4-hydroxyphenyl)butanoate (1.51g) as a pale yellow oil; NHR(CDCl3):
1.20(3H,t), 1.27(3H,d), 2.52(2H,q), 3.22(1H,m), 4.08(2H,q), 4.84(1H,s), 6.71(2H,m) and 7.08(2H,m); m/z 208(H). Ethyl 3-(4-allyloxyphenyl)butanoate was prepared using the procedue used to prepare ethyl 3-(4-allyloxyphenyl)propionate (see Example 1) but using ethyl 3-(4-hydroxyphenyl)butanoate in place of ethyl 3-(4-hydroxyphenyl)propionate; NhR(CDCl3) 1.17(3H,t), 1.25(3H,d), 2.51(2H,m), 3.22(1H,m), 4.05(2H,q), 4.50(2H,m), 5.33(2H,m), 6.06(1H,m), 6.82(2H,m) and 7.11(2H,m); m/z 249 (H+H).
Ethyl 3-(3-allyl-4-hydroxyphenyl)butanoate was prepared as for ethyl 3-(3-allyl-4-hydroxyphenyl)propionate as in Example 1 but using ethyl 3-(4-allyloxyphenyl)butanoate in place of ethyl 3-(4-allyloxyphenyl)propionate; microanalysis: found: C, 72.6; H, 7.80X; C15H2003 requires C, 72.6; H, 8.12%; m/z 249(H+H).
The compound of formula 2 (Z = O.S02CF3) was prepared as for ethyl 3-(3-allyl-4-trifluorosulphonyloxyphenyl)propionate in Example 1 using ethyl 3-(3-allyl-4-hydroxyphenyl)butanoate in place of ethyl 3-(3-allyl-4-hydroxyphenyl)propionate. There was thus obtained an oil;

W O 94/25459 ~ ~ 5 ~ 7 ~ ~ PCT/GB94/00910 NHR(CDC13): 1.17(3H,t), 1.41(3H,d), 2.55(2H,m), 3.30(1H,m), 3.46(2H,d), 4.08(2H,q), 5.12(2H,m), 5.90(1H,m) and 7.13(3H,m).

~A~PL~ 129 In a similar manner to that described in Example 97, but using isobutyryl chloride in place of pivaloyl chloride, there was obtained 3-[2-(4-dimethylacetyloxymethyl-2-allylphenyl)ethynyll-quinuclidin-3-ol as a solid, m.p. 68C; microanalysis, found: C, 75.5;
H, 8.0; N, 4.0X; C23H29N03 requires: C, 75.2; H, 8.0; N, 3.8X; NNR
(CDC13): 1.2 (6H, d), 1.4 (lH, m), 1.65 (lH, m), 2.1 (3H, m), 2.6 (lH, m), 2.8 (4H, t), 3.1 (lH, d), 3.3 (lH, dd), 3.5 (2H, d), 5.1 (4H, m), 5.9 (lH, m), 7.1 t2H, m) and 7.4 (lH, d), m/z 368 (H+H).

~SANPL~ 130 In a similar manner to that described in Example 97, but using ethyl malonyl chloride in place of pivaloyl chloride, there was obtained 3-[2-(4-carbethoxyacetyloxymethyl-2-allylphenyl)ethynyll-quinuclidin-3-ol as an oil, NHR (CDC13): 1.2 (3H, t), 1.4 (lH, m), 1.65 (lH, m), 2.1 (3H, m), 2.8 (4H, m), 3.1 (lH, d), 3.3 (lH, dd), 3.4 (2H, s), 3.5 (2H, s), 3.5 (2H, d), 4.2 (2H, q), 5.1 (4H, m), 5.9 (lH, m), 7.1 (2H, m) and 7.4 (lH, d), m/z 412 (n+H).

ES~NPL~ 131 Sodium borohydride (33 mg) was added to a solution of 3-12-(4-(2-dicarbethoxyethylenyl)-2-allylphenyl)ethynyl]quinuclidin-3-ol (306 mg) in ethanol (7 ml) whilst maintaining the temperature at 5C. The resulting mixture was stirred at 25C for 12 hours, filtered, and the ethanol was then evaporated. The residue was stirred with acetone (5 ml) and lH aqueous hydrochloric acid (2.75 ml) was then added. The resulting mixture was stirred at 25C for 3 hours and sodium hydrogen carbonate (250 mg) was then added. The mixture was extracted with ethyl acetate (3 x 15 ml). The ethyl acetate extracts were combined, washed with brine (15 ml), dried (Na2S04) and evaporated to give a residue which was purified by medium pressure column chromatography on alumina (N32-63) using a 49:1 (v/v) mixture of ethyl acetate and methanol as eluent to give ~ 607~

3-12-(4-(2-dicarbethoxyethyl)-2- allylphenyl)ethynyl]quinuclidin-3-ol as a solid, m.p. 89C; microanalysis, found: C, 70.8; H, 7.8; N, 3.1%;
C26H33N05 requires: C, 71.0; H, 7.6; N, 3.2%; NHR (CDC13): 1.2 (6H, t), 1.4 (lH, m), 1.65 (lH, m), 2.1 (3H, m), 2.8 (4H, t), 3.0 (lH, d), 3.1 (2H, d), 3.3 (lH, dd), 3.4 (2H, d), 3.6 (lH, t), 4.1 (4H, q), 5.1 (2H, m), 5.9 (lH, m), 7.0 (2H, m) and 7.2 (lH, d). m/z 440 (H+H).

~A~PL~ 132 Butyl Lithium in hexane (1.6 H, 3.4 ml) was added slowly to a stirred solution of trimethylsilylacetylene (1.0 g) in tetrahydrofuran (20 ml) at -70C under an atmosphere of argon. The reaction mixture was stirred at -70C for a further 60 minutes. A
solution of 3-12-{2-formylphenyllethynyl]-3-trimethylsilyloxy-quinuclidine (1.3 g) in tetrahydrofuran (10 ml) was added slowly to the reaction mixture vhilst maintaining the temperature at -70C. The reaction mixture was allowed to warm to ambient temperature and then stirred for 20 hours. The reaction mixture was evaporated, potassium carbonate (4 g) and methanol (50 ml) added and the mixture was stirred vigorously at ambient temperature for 60 minutes. The inorganic salts were removed by filtration and the filtrate was evaporated to give a residue which was dissolved in ethyl acetate (150 ml). The solution was extracted with 2H hydrochloric acid (2 x 100 ml). The aqueous extracts vere combined, washed with ether (2 x 200 ml) and then basified to pH9 by addition of 5N sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate (2 x 100 ml), the ethyl acetate extracts combined, washed with water (100 ml), brine (100 ml), dried (HgS04) and evaporated. The residue was purified by column chromatography on alumina (Alumina N 32-63) using a gradient of 2:98 to 5:95 (v/v) methanol in ethyl acetate as eluent to give a solid which was recrystallised from a mixture of tetrahydrofuran/hexane to give 3-12-{2-(1-hydroxy-1-ethynylmethyl)phenyl}ethynyll-quinuclidin-3-ol (110 mg), m.p. 217C; microanalysis; found: C, 74.6;
H, 7-2; N, 4-6%, C18HlgN02Ø5 H20 requires: C, 74.5; H, 6.9; N, 4.8%;
NHR: 1.2-1.4 (lH, m), 1.45-1.7 (lH, m), 1.8-2.05 (3H, m), 2.55-2.8 (4H, m), 2.85 (lH, d), 3.15 (lH, d), 3.38 (lH, dd), 5.58 (lH, s), W O 94/2S459 21 fi ~ 7 ~ ~ PCT/GB94/00910 5.6-5.7 (lH, m), 6.08 (lH, d), 7.25-7.46 (3H, m), 7.65 (lH, d), m/z 282 (~+H)-The 3-12-(2-formylphenyl}ethynyl]-3-trimethylsilyloxy quinuclidine used as starting material was obtained as follows.
Bis(triphenylphosphine)-palladium(II) chloride (175 mg) and copper(I) iodide (85 mg) were added to a solution of 2-bromobenzaldehyde (2.03 g) and 3-ethynyl-3-trimethylsilyloxy-quinuclidine (2.23 g) in dimethyl formamide (25 ml) and triethylamine (5 ml) at ambient temperature under an atmosphere of argon. The reaction mixture was stirred at ambient temperature for 21 hours. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (2 x 100 ml). The ethyl acetate extracts were combined, filtered, washed with water (2 x 100 ml), brine (100 ml), dried (HgS04) and evaporated. The residue was purified by column chromatography on alumina (Alumina N 32-63) using a 40:60 (v/v) mixture of ethyl acetate and isohexane as eluent to give 3-12-~2-formylphenyl)ethynyl]-3-trimethylsilyloxyquinuclidine as an oil (2.1 g), NHR: 0.00 (9H, s), 1.1-1.3 (lH, m), 1.35-1.54 (lH, m), 1.82-1.90 (lH, m), 2.5 (4H, t), 2.73 (lH, d), 3.07 (lH, d), 7.38-7.48 (2H, m), 7.5-7.6 (lH, m), 7.68-7.75 (lH, m), 10.2 (lH, s), m/z 328 (H+H).
The 3-ethynyl-3-trimethylsilyloxyquinuclidine used as starting material was obtained as follows.
3-Ethynyl-3-hydroxyquinuclidine (1.5 g) and imidazole (1.7 g) were stirred in dimethyl formamide (25 ml). Trimethylsilylchloride (1.35 g) was added slowly to the solution and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (150 ml) and the aqueous phase extracted with ethyl acetate (2 x 100 ml). The ethyl acetate extracts were combined, washed with water (2 x 100 ml), brine (100 ml), dried (HgS04) and evaporated to give 3-ethynyl-3-trimethylsilyloxyquinuclidine as an oil (1.8 g), NHR: 0.15 (9H, s), 1.2-1.38 (lH, m), 1.42-1.6 (lH, m), 1.65-1.9 (3H, m), 2.55-2.7 (4H, m), 2.76 (lH, d), 3.02 (lH, d), 3.55 (lH, s), mtz 224 (M+H).
A solution of 3-[2-(formylphenyl}ethynyll-3-trimethylsilyloxyquinuclidine (0.815 g) in tetrahydrofuran (5 ml) was W O 94/25459 216 ~ i 9 ~ PCT/GB94/00910 added slowly to a stirred solution of vinyl magnesium bromide (1.0 H
in tetrahydrofuran; 5ml) in tetrahydrofuran (50 ml) at ambient temperature. The reaction mixture was stirred and heated at reflux for 3 hours. The reaction mixture was evaporated and the residue dissolved in 2H hydrochloric acid (50 ml). The aqueous phase was washed with ether (2 x 100 ml) and then basified to pH9 by cautious addition of solid potassium carbonate. The mixture was extracted with ethyl acetate (2 x 100 ml). The ethyl acetate extracts were combined, washed uith water (100 ml), brine (100 ml), dried (HgS04) and evaporated. The residue was purified by column chromatography on alumina (Alumina N 32-63) using a 5:95 (v/v) mixture of methanol in ethyl acetate as eluent to give a solid which was recrystallised from acetonitrile to give 3-l2-1-(1-hydroxy-1-ethenylmethyl)phenyl}-ethynyl-3-hydroxy quinuclidine (117 mg), m.p. 148-149.5C;
microanalysis, found: C, 75.9; H, 7.5; N, 4.9%; C18H21N02 requires: C, 76.3; H, 7.5; N, 4.9Z; NHR: 1.2-1.4 (lH, m), 1.42-1.68 (lH, m), 1.7-2.0 (3H, m), 2.62 (4H, t), 2.85 (lH, d), 3.07 (lH, d), 4.95-5.07 (lH, m), 5.16-5.3 (lH, m), 5.45-5.56 (2H, m), 5.58 (lH, s), 5.86-6.08 (lH, m), 7.17-7.27 (lH, m), 7.3-7.4 (2H, m), 7.46-7.52 (lH, m), mtz 284 (h+H).

E~AnPLE 133 The ~-ketoester prepared in Example 51 (0.22g) was converted to its hydrochloride salt by dissolving in ethanol, and acidifying the resulting solution by adding ethanolic hydrogen chloride until the solution was pH1. The solvent was removed immediately and the residue was dissolved in anhydrous dimethylformamide (5ml) whilst under an atmosphere of argon. Sodium borohydride (0.044g) was added to the mixture and the mixture was stirred for 1 day. An excess of sodium borohydride was added to the reaction mixture followed by anhydrous ethanol (5ml). The reaction mixture was stirred overnight.
The reaction mixture was cooled with an ice-bath and quenched by careful addition of saturated ammonium chloride solution, whilst under an atmosphere of argon. The aqueous mixture was extracted with ethyl acetate (3 x 50ml). The ethyl acetate extracts were combined, washed with brine (50ml), dried (~gS04) and evaporated W O 94/25459 ~ 3 ~ 7 ~ ~ PCT/GB94/00910 to give a colourless oil (0.2g); m/z 354 (H-H). This oil was dissolved in acetone (5ml) and treated with ethanolic HCl, until the pH>l. The mixture was stirred for a few hours at room temperature.
The solvent was removed by evaporation and the residue was partitioned between saturated sodium carbonate solution (20ml) and ethyl acetate (20ml). The aqueous layer was further extracted with ethyl acetate (2 x 20cm3). The ethyl acetate extracts were combined, washed with brine, dried (HgS04) and evaporated to produce a crude oil. The oil uas purified by chromatography on silica gel (Varian Bond Elut Sl silica gel) using a 80:20:3 (v/v/v) mixture of ethyl acetate/ethanol/triethylamine as eluent to give 3-[2-(2-allyl-4-(1,2-dihydroxyethyl)phenyl)ethynyllquinuclidin-3-ol as a gum (0.05g); m/z 342(H+H).

e~AnPL~ 134 The procedure described in Example 97 was repeated using benzyl alchol (0.4g) and ethyl chloroformate as starting materials to give 3-12-(2-allyl-4-ethoxycarbonyloxymethylphenyl)ethynyl (0.04g);
m/z370(H+H).

e~A~PL~ 135 A solution of hydrogen chloride dissolved in ethanol was added to a solution of 3-[2-(2-allyl-4-(ethoxycarbonylethyl-carbonyl)phenyl)ethynyl]quinuclidin-3-ol (0.36g) in ethanol (5ml) to give a pH of 1. The mixture was evaporated and the residue was dissolved in ethanol (5ml). Sodium borohydride (0.3g) was added over a period of 4 hours. The reaction mixture was stirred overnight. The mixture was acidified with 2M aqueous hydrochloric acid. The mixture was filtered and the filtrate was evaporated. The residue was treated with acetone/ethereal hydrogen chloride mixture and then evaporated.
The residue ~as purified by chromatography on silica gel (Varian Bond Elut Sl silica gel) using an 80:20:3 mixture of ethyl acetate/ethanol/triethylamine as eluent to give 3-[2-(2-allyl-4-(1,4-dihydroxybutyl)phenyl)ethynyl]quinuclidin-3-ol (24mg) as a gum; m/z 355(H+H).

~ y~
W O 94/25459 ~ ~ PCT/GB94/00910 eSAnPL~ 136 The procedure described in Example 1 was repeated using 1-(methoxymethyl)-2-(trifluoromethylsulphonyloxy)benzene in place of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate.
There was thus obtained 3-[2-(2-methoxymethyphenyl)ethynyll-quinuclidin-3-ol as an oil; NhR(CDCl3): 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.02(3H,m), 2.6-2.8(4H,m), 2.82-2.92(1H,d), 3.05-3.15(1H,d), 3.4(3H,s), 4.62(2H,s) and 7.4(4H,m).

~AXPL~ 137 Illustrative pharmaceutical dosage forms suitable for presenting the compounds of the invention for therapeutic or prophylactic use include the following tablet and capsule formulations, which may be obtained by conventional procedures well known in the art of pharmacy and are suitable for therapeutic or prophylactic use in humans:-(a) Tablet I
m~/tablet Compound Z* 1.0 Lactose Ph. Eur. 93.25 Croscarmellose sodium 4.0 haize starch paste (5% w/v aqueous paste) 0.75 hagnesium stearate 1.0 (b) Tablet II m~/tablet Compound Z* 50 Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 haize starch 15.0 Polyvinylpyrrolidone (5% w/v aqueous paste) 2.25 hagnesium stearate 3.0 W 0 94/254~9 ~ 1 5 ~ 5 ~ ~ PCT/GB94/00910 (c) Tablet III m~/tablet Compound Z* 100 Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Haize starch paste (5% w/v aqueous paste) 2.25 Hagnesium stearate 3.0 (d) Capsule m~/cars~le Compound Z* 10 Lactose Ph.Eur. 488.5 Hagnesium stearate 1.5 Note * The active ingredient Compound Z is a compound of formula I, or a salt thereof, for example a compound of formula I described in any of the preceding Examples.

The tablet compostions (a) - (c) may be enteric coated by conventional means, for example, with cellulose acetate phthalate W O 94/25459 ~ ~ 6 0 7 9 ~ PCT/GB94/00910 SC~

(a) ~ C~ O

13~
~ 6f 1. CBr4/PPh3/Zn, CH2C12, ROOH TEHPERATURE
2. (a) n.BuLi (2 equiv), THF, -60C, ARGON ATHOSPHERE (b) H20 4. t. BuOK, t-BuOH, REFLUX

(b) ~ 2. ~ 3 '~`

1. H~/Pd -CaC03, EtOH
2 Ph3G~PCH3Br~ KOBu , THF
3 PHTHALIC ANHYDRIDE, BENZENE SULPHONIC ACID, 2~30C.

W O 94t25459 ~ ~ Q 7 ~ ~ PCT/GB94/00910 SCHEX~ 2 (a) ~ 0 ~ 0-1 ,~

1. H2/Pd-CaC03, ETOH
2. (a) H2C=CHHgBr, THF, 20-25C (b) NH4C1 solution (b) ~ ~,ecs ~ ~

1. Me3Si-C--C-Li, THF, -70C to -75C, ARGON ATHOSPHERE
2. K2C03, HeOH, 20-25OC

~1~07~a' SCHE~E 3 I-Ar-OH + MeOCH2CH2Br ~ I-Ar-OCH2CH2ONe DHF

O LiH
Br-Ar-OH + ~ o ~ Br-Ar-OCH2CH2OH
DHF
/ NaOH, CH2Cl2 e2S4 PhOH /

Ph3P, / V
DEAD / - Br-Ar-ocH2cH2oMe Br-Ar-OCH2CH20Ph PhCH20-Ar-OH + BrCH2C02Et > PhcH2o-ArocH2co2Et ACETONE H2/ Pd/C

HO-Ar-OCH2C02Et I-Ar-OH + BrCH2CH20He ~ I-Ar-OCH2CH2OHe DHF

Br-Ar-OH + H2C = CHCH2Br~ Br-Ar-OCH2CH=CH2 ACETONE
CLAISEN
Ph20, HEAT (eg. 250C) BrCH2C02Et ~
Br-Ar-OcH2cO2Et ~ Br-Ar-OH
K2C03 H2CH=CH2 CH2CH=CH2 Acetone W O 94/25459 ~ 5 ~ PCT/GB94/00910 SCH~ 4 Ar(cH2)mcHo + H2C(C02H)2 ~ Ar(CH2)mCH2C02H
2.

1. base, eg. NaOH or pyrollidine 2- H2,Pd/C

Ar(CH2)mCOR 1 ~ Ar(CH2)mC(R l)=CHCO2R

~ Ar(CH2)mCH(Rll)CH2C02R

1. Ph3P CH2=CO2R Br , KOBut/THF
2- H2, Pd/C

2~(~07')-~

CII~IICAL ~OR~

R' }Ar (I) ~ (Ia) ~X-Ar ( II ) Ar-11 ( III ) ~ ~ (IV) ~(~ (V) Ar-NH2 (VI) Ar-CHO (VII) ~1 (VIII) Ar-Z (IX) /~\Q..
--l~ f 2 3 (XI) ~Lc~
Ar-CH~H ( XII ) ~J, ( XIII ) WO 94/25459 ~ 7 ~ ~ PCT/GB94/00910 CIIEXIC~L ~ORWI~

ArCH2Z (XIV) I <~ (XV) ~1 ~\R

ArYH ( XVI ) [~ L ( XVI I ) ~ \R~

R` o~

(XVIII) Q

Ar-C----cn ( XIX ) ~C-C~
~,, (XX) ~' ~>J, ( XXI ) ~Q~

~CH=C-SnL3 (XXII ) ,L

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, (I) wherein:
R1 is hydrogen or hydroxy;
R2 is hydrogen; or R1 and R2 are joined together so that CR1-CR2 is a double bond;
X is selected from -CH2CH2-, -CH=CH-, -CC-, -CH2O-, -OCH2-, -CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (wherein n is 0,1 or 2);
Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, carbamoyl, (1-6C)alkylcarbamoyl, di-[(1-6C)alkyl]carbamoyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6C)alkyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di[(1-6C)alkylcarbamoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy;
and wherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives. provided that when X is -OCH2-, -NHCH2- or -S(O)nCH2- (wherein n is 0,1 or 2), then R1 is not hydroxy; and provided that when a substituent on Ar includes a phenyl moiety, X is -OCH2-, then R1 and R2 are not both hydrogen, or joined together so that CR1-CR2 is a double bond.

2. A compound as claimed in claim 1 wherein R1 is hydroxy and R2 is hydrogen.

3. A compound as claimed in claim 1 or 2 wherein Ar is phenyl which bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-[(1-6C)alkoxy(1-6C)alkyl](1-6C)alkoxy, phenoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxycarbonyl, di-[(1-6C)alkoxy](1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl, di-[(1-6C)alkyl]amino(1-6C)alkyl, (1-6C)alkylcarbonylamino(1-6C)alkyl, (3-6C)cycloalkyl(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, phenyl(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl;
(1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, cyano(1-6C)alkoxy, cyano(1-6C)alkoxy(1-6C)alkyl, nitro(1-6C)alkoxy, nitro(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylthio, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)-alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkyl, carboxy(1-6C)alkyl, hydroxy(1-6C)alkyl (1-6C)alkylamino(1-6C)alkyl, di-[(1-6C)alkyl]amino(1-6C)alkyl, (1-6C)alkylamino(1-6C)-alkoxycarbonyl(1-6C)alkyl, di-[(1-6C)alkyl]amino(1-6C)-alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylcarbamoyl(1-6C)alkoxycarbonyl, di-[(1-6C)alkyl]carbamoyl(1-6C)alkoxycarbonyl, carbamoyl-(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, di-[(1-6C)alkyl]amino(1-6C)alkoxycarbonyl, (1-6C)alkoxy-carbonyl(1-6C)alkanoyl, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, (2-6C)alkynyl(1-6C)alkoxy(1-6C)alkyl, halogeno(1-6C)alkyl-(1-6C)alkoxycarbonyl, phenoxycarbonyl, di-[(1-6C)alkoxycarbonyl]alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyloxy(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkanoyloxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl-(1-6C)alkyl, hydroxy(1-6C)alkoxy, di-hydroxy(1-6C)alkyl, hydroxy(2-6C)alkenyl, hydoxy(2-6C)alkynyl, (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; and, in addition, optionally bears one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.

4. A compound as claimed in any one of the proceeding claims wherein Ar is phenyl which bears one or more substituents selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, hydroxy(1-6C)alkyl, (1-6C)alkanoyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl and carboxy(1-6C)alkyl; and optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.

5. A compound as claimed in claim 1 wherein R1 is hydroxy, R2 is hydrogen, X is selected from -CH2CH2-, -CH=CH-, -CC- and -CH2O-(especially -CC-); Ar is phenyl which bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-[(1-6C)alkoxy](1-6C)alkoxy, (1-6C)alkoxycarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkoxycarbonyl, (1-6C)alkylthio(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkylcarbamoyl, (1-6C)alkoxy(1-6C)alkylcarbamoyl, (1-6C)alkanoyloxy(1-6C)alkyl, cyano(1-6C)alkoxy, carboxy(1-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkanoyl, (1-6C)alkylthio(1-6C)alkyl, (2-6C)alkenyl(1-6C)alkoxy(1-6C)alkyl, and (1-6C)alkanoyl(1-6C)alkyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives; and wherein Ar may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives.

6. A compound as claimed in claim 1 wherein R1 is hydroxy, R2 is hydrogen, X is -CC-, Ar is phenyl which bears a substituent selected from methoxyethoxycarbonylethyl, methoxypropyl, ethoxycarbonylethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, iso-butoxycarbonylethyl, hexyloxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylpentyl, methoxycarbonylmethoxy, methoxyethoxy, methoxyethoxymethyl, methoxyethoxyethyl, carboxyethyl, carboxypropyl, hydroxymethyl, ethanoylethyl, ethoxycarbonylethanoyl, ethoxycarbonylpropanoyl; and optionally one or more substituents selected from (1-6C)alkyl, (2-6C)alkenyl, halogeno, (1-6C)alkoxy and (1-6C)alkanoyl.

7. A compound as claimed in any one of the preceding claims wherein Ar is phenyl which bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, and which optionally bears one or more substituents selected from the optional substituents defined in claim 1.

8. A compound as claimed in claim 7 wherein R1 is hydroxy, R2 is hydrogen, X is -CC-, Ar is phenyl which bears a substituent selected from (1-6C)alkoxycarbonyl(1-6C)alkyl and carboxy(1-6C)alkyl, and optionally bears a (2-6C)alkenyl group.

9. A compound of formula I, or a pharmaceutically acceptable salt thereof, (I) wherein:
R1 is hydrogen or hydroxy;
R2 is hydrogen; or R1 and R2 are joined together so that CR1-CR2 is a double bond;
X is selected from -CH2CH2-, -CH=CH-, -CC-, -CH2O-, -OCH2-, -CH2NH-, -NHCH2-, -CH2CO-, -COCH2-, -CH2S(O)n- and -S(O)nCH2- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanoyloxy, N-(1-6C)alkylcarbamoyl, N,N-di[(1-6C)alkylcarbamoyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, phenyl, phenoxy, cyano, nitro, and hydroxy;
and wherein Ar and/or a phenyl moiety in any of said groups mentioned above may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives;
provided that when X is -OCH2-, -NHCH2- or -S(O)nCH2- (wherein n is 0,1 or 2), then R1 is not hydroxy; and provided that when a substituent on Ar includes a phenyl moiety, X is -OCH2-, then R1 and R2 are not both hydrogen, or joined together so that CR1-CR2 is a double bond.

10. A compound as claimed in claim 9 wherein R1 is hydroxy, R2 is hydrogen, X is selected from -CH2CH2-, -CH=CH-, -CC- and -CH2O-;
Ar is phenyl which bears one or more substituents independently selected from (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkyl, di-[(1-6C)alkoxy(1-6C)alkyl](1-6C)alkoxy, phenyloxy(1-6C)alkoxy, phenyl(1-4C)alkyl and (1-6C)alkoxy(1-6C)alkoxycarbonyl; and Ar optionally bears one or more further substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino N-(1-6C)alkylcarbamoyl, di-N,N-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oxime derivatives;

11. A compound as claimed in any one of claims 1 to 6, 9 or 10 wherein X is selected from -CC-, -CH2CH2-, -CH2O- and -CH=CH-.

12. A compound as claimed in claim 11 wherein X is -CC-.

13. A compound as claimed in claim 1 wherein the compound is selected from:
3-[2-(2-allyl-4-(2-ethoxycarbonylethyl)phenyl)ethynyl]quinuclidin -3-ol;
3-[2-(2-allyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl]quinuclidin -3-ol;
3-[2-(2-allyl-4-(3-methoxycarbonylpropyl)phenyl)ethynyl]quinuclidin -3-ol;
3-[2-(2-allyl-4-(4-methoxycarbonylbutyl)phenyl)ethynyl]quinuclidin -3-ol;
3-[2-(2-allyl-4-(2-iso-butoxycarbonylethyl)phenyl)ethynyl]quinuclidin -3-ol;
3-[2-(2-allyl-4-(2-(2-methoxyethoxycarbonyl)ethyl)phenyl)ethynyl]-quinuclidin-3-ol;
3-[2-(2-allyl-4-(3-methoxypropyl)phenyl)ethynyl]quinuclidin-3-ol;
3-[2-(2-allyl-4-(2-hexyloxycarbonylethyl)ethynyl]quinuclidin-3-ol;
3-[2-(2-allyl-4-(2-methoxycarbonyl-2-methylethyl)phenyl)ethynyl]-quinuclidin-3-ol;
3-[2-(2-allyl-4-(2-carboxyethyl)phenyl)ethynyl]quinuclidin-3-ol;
3-[2-(2-allyl-4-(5-methoxycarbonylpentyl)phenyl)ethynyl]quinuclidin--3-ol; and 3-[2-(2-allyl-4-(2-carboxypropyl)phenyl)ethynyl]quinuclidin-3-ol;
and pharmaceutically acceptable salts thereof.

14. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, as claimed in claim 1 which process comprises:
(a) for these compounds of formula I in which R1 and R2 are both hydrogen, reducing a compound of formula I in which R1 and R2 are joined together so that CR1-CR2 is a double bond;
(b) for compounds of formula I in which R1 and R2 are joined together so that CR1-CR2 is a double bond, dehydrating a compound of formula I in which R1 is hydroxy and R2 is hydrogen;
(c) for compounds of formula I in which R1 and R2 are joined together so that CR1-CR2 is a double bond, treating a compound of formula II

(II) in which Z is a leaving group with a base;
(d) for those compounds of formula I in which X is -CH2CO-, reacting an organometallic compound of formula III:

Ar-M (III) in which M is a metal atom or a derivative thereof, with a compound of formula IV:

(IV) e) for those compounds of formula I in which X is -CH2-NH- or -NHCH2-, reducing a compound of formula I in which X is -CH=N- or -N=CH- (as appropriate);
f) for those compounds of formula I in which X is -CH2NH-, -CH2O-, -CH2S-, R1 is hydroxy and R2 is hydrogen, reacting a compound of formula IX:

Ar-Z (IX) in which Z is -NH2, -OH or SH as appropriate with a compound of formula X:

(X) g) for compounds of formula I in which X is -CH=CH-, reacting a compound of formula XI:

Ar-CH2?Ph3W? (XI) with a compound of formula V:

(V) in the presence of a base;
h) for those compounds of formula I in which X is -CH2CH2-, reducing a compound of formula I in which X is -CH=CH- or in which X
is -CC-;
i) for compounds of formula I in which X is -COCH2-, reacting a compound of formula XII:

Ar-CH2M (XII) in which M is a metal atom or a derivative thereof, with a compound of formula XIII:

(XIII) j) for those compounds of formula I in which X is -CH2O- or -CH2S-, reacting a compound of formula XIV

ArCH2Z1 (XIV) with a compound of formula XV

(XV) in which Z1 is a leaving group and Z2 is -YM, or Z1 is -YM and Z2 is a leaving group, and wherein Y is oxygen or sulphur (as appropriate) and M is a metal atom;

k) for those compounds of formula I in which X is -OCH2- or -SCH2- and R1 and R2 are both hydrogen, reacting a compound of formula XVI:

ArYH (XVI) in which Y is oxygen or sulphur as appropriate with a compound of formula XVII

(XVII) in which Z is a leaving group;

l) for compounds of formula I in which X is -OCH2-, -SCH2-, -CH2O-, or -CH2S-, deprotecting a compound of formula XVIII

(XVIII) in which Q is a protecting group;
m) for those compounds of formula I in which X is -CC-, reacting a compound of formula I in which X is -CH=CH- with a halogen, followed by treatment with a base;
n) for those compounds of formula I in which R1 is hydroxy, R2 is hydrogen and X is -CC-, reacting a compound of formula XIX:

Ar-CCH (XIX) in which M is a metal atom, with quinuclidin-3-one;
o) for those compounds in which R1 and R2 are hydrogen and X is -CC-, reacting a compound of formula XIX

Ar-CCH (XIX) in which M is a metal atom with a compound of formula XV

(XV) in which Z is a leaving group;

p) for those compounds in which X is -CC- and R1 is hydrogen or hydroxy and R2 is hydrogen, reacting a compound of formula XX:

(XX) with a compound of formula IX:

Ar-Z (IX) in which Z is a leaving group in the presence of a catalyst;

q) for those compounds in which X is -C=C- and R1 is hydrogen or hydroxy and R2 is hydrogen, reacting a compound of formula XXI:

(XXI) with a compound of formula IX:

Ar-Z (IX) in which Z is a leaving group in the presence of a catalyst;

q) for those compounds in which X is -C=C- and R1 is hydrogen or hydroxy and R2 is hydrogen, reacting a compound of formula XXI:

(XXI) with a compound of formula IX:

Ar-Z (IX) in which Z is a leaving group in the presence of a catalyst;

r) for those compounds in which X is -CH=CH-, reducing a compound of formula I in which X is -CC-;

s) for those compounds of formula I in which X is -CH=CH-, reacting a compound of formula XXII:

(XXII) in which L is a suitable ligand with a compound of formula IX:

Ar-Z (IX) in which Z is a leaving group in the presence of a catalyst;

and whereafter, when a pharmaceutically-acceptable salt is required, reacting the compound of formula I with an acid which affords a physiologically acceptable anion or a base which affords a physiologically acceptable cation.

15. A pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims together with, or in admixture with, a pharmaceutically acceptable diluent or carrier.